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Philip Morris

Report A0500/3017.09 Pharmacological Effects of Nicotine Derivatives (Synthetic Compounds) on the Isolated Rabbit Aortic Strip

Date: 15 Dec 1981
Length: 165 pages
1002939218-1002939382
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SCRT, SCIENTIFIC REPORT
BIBL, BIBLIOGRAPHY
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PAGES,ROBERT/MICROFICHE
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R4
Named Person
Su, C.
Bevan, J.A.
Bhadrakom
Furchgott
Levin, J.A.
Nedergaard, O.A.
Schrold, J.
Suzuki, A.
Recipient (Organization)
Ftr, Fabriques De Tabac Reunies S.A.
Recipient
Rylander, R.
Named Organization
Hewlett Packard
Hugo Sachs Electronic
Author (Organization)
Inbifo, Institut Fur Biologische Forschung
Litigation
Stmn/Produced
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FLGE, GERMAN LANGUAGE
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02 Apr 1999
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kkc87e00

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DR. MED. R._ FIYLANDER _~_. .. _..._ c/o.FAB9IQUES_ PE TAgAC.REUNIES S.A. ! SWI TZERLAND,.-' REPORT A 0500/3017.09 PHARMACOLOGICAL EFFECTS OF 15.DEC.81 DRBL/DRMO/RM : COPyNO.:' NICOTINE DERIVATIVES (SYNTHETIC COMPOUNDS) ON THE lSOLATED RABBIT AORTIC STRIP
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INBIFO Institut fOr biologische Forschung • Ktlln REPORT A o5oo/3o17.o9 RL53 (R),B7 PAGE o-1 CONTvNTS PAGE 1 SUMMARY 1-1 1.1 Objective 1i_1 1.2 Results lr1 TABLE 1: CONTRACTION ACTIVZTY 1-3 2 RESPONSIBILITY 2-1 3 INTRODUCTIiON 3-1 4 SUBSTANCES 4-1 4.1 Test Substances 4-1 4.2 Reference Substance 4-19 4.2.1 Nicotinehydrogen-(+)-tartrate 4-19 4.2.2 Noradrenaline 4-2o 5 METHOD 5-1 5.1 Animals 5-1 ~ 5.2 Animal Housing 5-1 5.3 Food and Drinkinq Water 5-2 5.4 Dissolvilnq,of Substances 5-2 5.5 Pr-zparatiom of the Aortic Strips 5-4 5.6 Exe::ution of the Experiment 5-7 5.7 Gas Chromatoqraphic Determination of Purity of "SYNTHETIC COMPOUNDS" 5-12 5.8 Thin Layer Chromatographic Determination of Purity of "SYNTHETIC COMPOUNDS" 5-14 :'IGURE A: LEVER 5-9 TABLE A: TZST CYCLE 5-11 »"we
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INBIFO Institus. fC.r ",soirynische Forschung • Ktlln REPORT A o500/3017.09 RL53 (R) B8 PAGE o-2 CONTENTS (continued) PAGE 6 EVALUATION 6-1 7 STORAGE OF MATERIALS AND RECORDS 7-1/8-1 8 RESULTS 7-1/8-1. 8.1 Text 7-1/8-1 8.2 Tables and Figures TABLE ® CONTRACTION (o/o)~, EFFECTIVE CONCENTRATION AND RATIO of EFFECTIVE CONCENTRATION 2 AMPLITUDE ON THE RECORDER, CR-14o8' 3.1.1 to 3.1.3 w CR-1523 3.2.1 to 3.2.8 w CR-1652 3.3.1 to 3.3.11 w CR-177oA 3.4.1 to 3.4.9  CR-1772 3.5.1 to 3.5.16 0 w CR-1316A 3.6.1 to 3.6.4 CR-1773 3.7.1 to 3.7.3 w CR-1274 3.8.1 to 3.8.8 CR-1766A 3.9.1 to 3.9.8 U REFERENCE SUBSTANCE 3.1!0.l to 3.1o.3o 3? KW6,
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INBIFO Institut fur biologische Forschung • Ktllm REPURT A o5oo/3o17.o9 RL53 (R)~B9 PAGE o-3 CONTENTS (continued) TABLE CONTRACTION RELATIVE TO MAXIMUM NICOTINE CONTRACTION (o/o), CR-14o8 4.1 " CR-1523 4.2 "' CR-1652 4.3 " CR-177oA 4.4 " CR-1772 4.5 ® " CR-1316A 4.6 " CR-1773 4.7 " CR-1i274 4.8 " CR-1766A 4.9 " REFERENCE SUBSTANCE 4.10 FIGURE CONCENTRATION/RESPONSE CURVE, CR-1274 1 " CR-1523 2 " CR-1i652 3' ~ " CR-1i766A 4 " CR-177oA 5 " CR-1772 6 " L-NICOTINE BIS(HYDROGEN)i- L-TARTRATE 7 PAGE 9 REFERENCES This report contains, including front page, 166 pages. 9-1
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INBIFO Institut fOr biologische Forschung • Kblh REPORT A o5oo/3o17.o9 RL53 (R) A7 1 SUMMARY 1.1 Obiective PAGE 1i-1 The "SYNTHETIC COMPOUNDS" CR-1274, -11316A, -1408, -1523, -1652, -1766A, -177oA, -1'772, -1773 and the reference substance L-nico- tine bis (hydrogen)-L-tartrate should be examined for their contraction activity on the isolated rabbit aortic strip. The ~ effective concentration and the ratio of the effective concentra- tion for the reference substance over that for the respective test substance should be determined. The effective concentration of a substance is that mol~ar concen- tir_ion which evokes 5o percent of the maximum nicotine contrac- tion. The maximum nicotine contraction is that contraction elicited' by 316 micromol/l nicotine (- reference substance). The. concentration/response curve for the reference substance, included in this report, shows that this concentration did ellicit the maximum nicotine contraction. The experiments are performed according to Furchgott and' Bhadra- ® kom (1953)1, modified. 1.2 Results (see TABLE 1) For the reference substance the effective concentration is 28.7 micromol/1. i? •~ei
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INBIFO Institut fur biologische Forschung • Ktlln REPORT A o5oo;/3o17.o9 RL53 (R) AS PAGE 1-2 Alkylated nicotines: The effective concentration for CR-1652 (5,6-dimethylnicotine)~ is 12.1 micromol/l. This is approx. 11/2 of the effective concentration for the reference substance. For CR-1772 (R,S-6-ethylnicotine) the effective concentration of 34.8 micromol~/1 is approx. equal to that of the reference sub- stance. At the highest concentration applied, i. e. 562 micro- mol/1, the test substances CR-1523 (:R,S-5-methylnicotine), and CR-177oA (R,S-5-ethylnicotine) elicited only 3o.9 percent and 38.5 percent respectivel~y of the maximum nicotine contracti.n. No ~ response was seen with CR-14o8 (di,1-2-methylnicotine) at the highest concentration applied (562 micromol/1). Anabasines: No response was seen with CR-1316A (1-N-methyianaba- sine) at the hig,hest concentration applied (562 micromol/1). N-oxide: No response was seen with CR-1773 ((S)-nicotine-N-oxide) at the hig,hest concentration applied (562 micromol/1). Not classified substa;ices: Test substance CR-1274 (d,l-N-methyl- 2-(beta-pyridyl)azetidine) showed an effective concentration of 9o.9 micromol/l, which is approx. 3 times that for the reference substance. The effective concentration for CR-1766A (R,S-1- ~ methyl-3-(3-pyridyl)pyrrollidine): is 178.o micromol/1 i. e. approx. 6 times that for the reference substance. Ratio: The ratios of the effective concentration r..,)r the reference subs`ance over that for the test si.bstances CR-1766A, -1274, -1772 and -1652 are o.162, o.316, ~.825 andi2.37 respectivel~y.
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REPOtzT A o50o/3o17.o9 RL53 (R) AS PAGE 1-3 CHEMICAL CLAS&IFICAT'ICN OF CDMPOtND CR-t40. EFFECTIV£ OONCFNiRATION (a) RATIO OF EFFECTIVE CoNCkNIRATION REF. SUBSTANCE CD[IPRACTICN RELATIVE TO MAXIMm NicDTINE CONPRACPION (= loo %) AT MAXIMAL ('ONCE_NTRATION Ic G Q ~ TIST SUE3STANCE APPLIED (ofo) (unol/1) 0 ~ ~ co alkylate6 14o8 0 562 ~ 0 niaotines 1523 3o.9 562 ~ ~ 1652 12.1 2.37 =r 177oA 38.5 562 E ~ 1772 34.8 o.825 re anabasines 1316A 0 562 A N-oxide 1773 0 562 a_ M not classified 1274 90.9 o.316 substances 1766A 178.o o.162 reference substance 28.7 (1) TABLE 1 CONPRACTION ACTIVITY (a) the effective concentration of a substance is defined 5o o/o of the maximum nicotine contraction that molar concentration which evokes END OF SUMMARY VzzsCszooi
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ItVBIFO Institut fgr biologische Forschung • MIm REPORT A o5oo/.io17.o9 RL53 (R) A9 PAGE 2-1! 2 RESPONSIBILITY saaaa~saaaaaaa Supervision of experimental conduct and evaluation: Dipl.-Biol. Dr.rer.nat. J. Biilmeyer Dipl.-Biochem. Dr.rer.nat. A. du Moulin ® Editorship: Dipl.-Biochem. Dr.rer.nat. A. du Moulin Experimental period: 27.Feb.8o to 8.Jul.8o 23.Feb.81 to 11.Mar.81 0 ».«A,
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iNBIFO Institut fiir biolbgische Forschung • K6In REPORT A o5oo/3o1'7.o9 RL53 (R) Alo 0 3 INTROD[JCTION PAGE 3-1i For the investigation of the action of acetylcholine and L- nicotine on vascuLar smooth muscle, often strips of rabbit pulmonary artery or the thoracic aorta have been used (a). To our knowledCe only for the pulmonary artery of the rabbit it is reported that this preparation is free of sympathetic ganglia, therefore the sympathomimetic contractile effects of acetyl- choline and' L-nicotine are assumed to be indirect (Nedergaard, O.A., Schrold, J. (1'977)). It has been shown that acetylcholine and L-nicotine act on presynaptic hexamethonium sensitive recep- tors, thereby releasing noradrenaline, which evokes a rapid contraction. This contraction ia transient, presumably because the concentration of the noradrenaline released is dimd':zished by reuptake into the nerve terminal and/or metabol_sm (Levin, J.A. (11i974)). Noradrenaline added to the aortic strip evokes a sustained contraction. (b) Pretreatment of a rabbit with reserpine, an agent known to deplete the noradrenaline stores, abolishes the noradrenaline ® release and results in loss of response to L-nicotine (Su, C., Bevan, J1.A. (197'0), Bevan, J.A., Su, C. (1972), Suzuki, A. et al. (,1973)). (a) Dr. Billmeyer introduc•9 the isolated' rabbit aortic strip in 1978 for testing nicotine derivatives (synthetic compound:)) in this laboratory. (b) It is generally assumed that the sympathomimetic contractile effects of acetylcholine and L-nicotine on the thoracic aorta are indirect as on the pulmonary artery. t 's~;::a~::~.-~ I
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INBIFO Institut tur biologische Forschung • K(Sin REPORT A oSoo/3o17.o9 RLS3 (R) All PAGE 4-1i 4 SUBSTANCES esaaasaaaa 4.1 Test Substances Date of receipt: 17.Aug.79 CR-number: CR-1274 Rell. mol. mass: 148.2o ta) ~ Source: Philip Ntorri's Research Center Batch no.: - Quantity: o.18 g Delivery container(s): ampul Description of test substance: clear, yellowish liquid Storage: stored in exsiccator under nitrogen inside refrigerator ® Changes during storage (time from receipt of substance until its use): no changes noticed INBIFO substance no.: S 272o Al (a) Relative mol~ecular mass of 148.2o rounded to the next W24 f igure i~s 147. Jr.ne, I
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PHILIP 140RRIS RESEARM CENTER Known Q Lit. Ref. Name dl-N-Idet.-hyl-2-(D-pyridyl)lzetidine 0 Emp. Formula C9H1?N2 Mol. Weight 148.20 NBa 6026 PG;r 60 Solubility • H20 very soluble Sample ti 6026-60B' Or.heiEtOH; hexane, methylenn ch1oY MP BP 45-50°r'O~.05 mm., So1n. in ' has pH - 92' 1924. 893' Pate Lata To be tested for (amounts supplied; 7-_J-72 ;~ _F 7- U)-72 OK It'-'2-72 OK 7-I)-7?1 Cl( From Calbraith Comments: Calccl_ Pound' c 72.94 72.85 H 8.16 8.07 AI 18'. 90 18. 73' U'ntc _a/2'"S!//'L Sub!aitter /tpp roved_- Available marerial tJill. he convert.c to a salt for screenino. /l/ 11// _ ~_M Prnjeet ;r` 2511(i
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INBIFO Institut fur biologische Forschung • K6In REPORT A o500/3o?7.o9 RL53 (R) A12 Date of receipt: CR-number: Rel. mol. mass: Source: Batch no.:. ® Quantity: Delivery container(s): Description of test substance: Storage: ® Check on purity, date: Changes during storage (time from receipt of substance until its use): INBIFO substance no.: PAGE 4-3 19.Aug.79 CR-1316A 176.26 (a) Philip Morris Research Center 1.0 g ampul clear colorless liquid stored in exsiccator under nitrogen inside refrigerator -_ gas chromatography,,-6. to to.Mar.81, main component, Apiezon L : 99.7 0/0 main component, - CaxbiWax 2oM: 99.2 0/0 thin Layer chromatography, 6.Mar.81, 1 spot no changes noticed S 232o B (a)i Relative molecular mass of 176.26 rounded to the next W24 figure is 178. 3/RAq1
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PHILIP MORRIS RESEARCH CENTER NB#6890 Pg1~ Sample # 6890-4A 2SP BP 63-4"/0.025 mm Recrystallization, GC,TLC Data: TLC (85:141:1; CHC1'3:EtOH:NH,OH)
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INRIFOJnstitut fur biologische Forschung • Kbin REPORT A o500/3o17.o9 RL53 (R) A13 Date of receipt: CR-number: Rel. mol. mass: Source: Batch no.: ~ Quantity: Delivery container(s): Description of test substance: Storage:__ Check on purity, date: Changes during storage (time from receipt of substance until its use): IN1aIF0 substance no.: PAGE 4-5 28.Ju1.78 CR-14o8 176.25 (a) Philip Morris Research Center 2 ampuls containing a total amount of o.66 g ampul clear lemon liquid stored' in exsiccator under nitrogen inside refrigerator gas chromatography, 6. to 9.Mar.81, main component, Apiezon L : 99.5 0/0 main component, Carbowax 2oM: 99.9 0/o thin layer chromatography, 6.Mar.81i, 1 spot no changes noticed S 2328 C1 and S 2328:C2 (,a) Relative molecular mass of 176.25 rounded to the next W24' f igure is 178. +nNe~ ~
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~ REPORT A o500/3017.09 PAGE 4-6 PHILIP MORRIS RESEARCH CENTak' New 'F.~( Known Q, Lit. Ref. dl-2-Methylnicotine STRUCTURE: N'-CH,B!r + Emp. Forasula C, , H i 5P12. Mol. Weight 175.25 METHOD OF PREP: D?IISO H'. CR-'.;08 NBtE 6641 Pg 4~ 97 Sample . 6641 -97e '.''? BP 56° /Q.11 mm 0 i Number I Date 26098 5,15 75 4' 152 7 364,5R j5J27/75 . Solvent TF NEAT CDC11, A^al. lk5-7797 From Galbraith Date 5L23/75 Colcd. Found'. C 7r,_95 75,n4' tE 9.15 9.06 15.68 + LAHI . Sulubility• To be tested for (amounts supplied): General screen 1.17 g available Derivatives: 1. dlipicrate, n.p. 229-230' 2. oxidized and esteritied to give methyl 2-mathjl- nicotinate Recrystallization, GC, TLC Data: TLC 85:1i4:1, CHC1a, HtOH, 194I=.oN1 R; 0.67 ~ II /Coc:L-ner.t5: C'tl_e 57'7~ Submicter Project ik2501~ Approved .<~.
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TABLE A: TEST CYCLE 3,Kwe, INBIFO Institut fur biolbgische Forschung • KOIn REPORT A o5oo/3o17.o9 RL53 (R) A14 Date of receipt: CR-number: Rel. mol. mass: Source: Batch no.: ~ Quantity: DeLivery container(s): Description of test substance: Storage: ® Check on purity, date: Changes during storage (time from receipt of substance until its use),: INc.;P-1 substance no.: 5-11 PAGE 4'-7. 16.Aug.79 CR-1523 176.25 (a) Philip Morris Research Center o.14 g, ampul clear yellow liquid stored in exsiccator under nitrogen inside refrigerator ..-gas chromatography, 6. to 9.Mar.81,---- main component, Apilezon L : 96.7 0/0 main component, Carbowax 2oM: 98.o o/o thin layer chromatography, 6.Mar.81,. 1 main spot, 2 faint spots no changes noticed S 2498 B (a) Relative molecular mass of 176.25 rounded to the next W24 figure is 178. 3-.«e'
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PAGE 4-8' Emp. Formula C, LIs N 2. ! Mol. Weight 176.25 NB# 712o Pg# 32 Solubility: _ sl. sol. H,0 Sample # 7126-32B MP BP 69-70°/0.04 mm I Number Date Solivent To be tested Yor (amounts supplied): . 27,000 0/30/77 TF 1.0 g 6369 15/3/77 CDC1 Derivatives: 6378 6/7/77 CDCIa dipicrate, mp 216-21'7° Anal'. # ' Z-5127 From Galbraith Date 6/23/77 Calcd. Found C 74.95 74.98 H 9.15 9.50 - N 15.90 '.-0T Recrystallization, GC,,TLC Data: Rf 0.72 (85-14-1); RTi 6.6 min. 5.', 5% SE 30 @ 125°-10°/mim. Comments:'
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This report contains, including front page, 166 pages.. ]7KWn INBIFO Institut fur biolbgische Forschung • K?5In REPORT A o5oo/3o17.o9 RL53 (R), A15 PAGE 4-9 Date of receipt: 17.Aug.79 CR-number: CR-1!652 Rel. mol. mass: 19o.28 (a) Source: Philip Morris Research Center Batch no.: - ® Quantity: 4 ampuls with o.1 g each Delivery container(s): ampull Description of test substance: clear colorless liquid Storage: stored in exsiccator under nitrogen inside refrigerator Changes during storage (time from receipt of substance until its use): no changes noticed ~ INBIFO substai,ce no.: S 2721 Al to A4' (a) Relative molecular mass of 19o.28 rounded to the next W24 figure is 196. ,n.LN'
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PHILIP MORRIS RESE.4RCH CEr}TER Samplc? 17' _ 77'[7,-11t 1', 1 rM EuoVer,t,;,,a 0 S So'_ :-ent Anal. # E-70.33 FromG.ilbrai th Date lll/27/7& dipicrata,Z277-L.15c CaUcd. Found 44.45 4V;.59 3.73 3./5 Emp. Fortr:ulaCrzHrIITli Mol. Weight 190.28 Solubi:ity: CH,CI,, CHC1,,, H',(1 (C.4ral . ~ To be tested Yor (amounts supplied) GENERA,L SCREEN Derivatives: dipicrate, 727J'-115c : mp 235-240° (deco Recrystallization, GC, TLC Data: ^ TLC: R'F = M01(B6:l4:l, CHCfil-EtOH -N' ,0I1)'. CommFnts; Submitter - I. ,.,. .11 -12!!=
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.v--..y v.-... Dipl.-Biochem. Dr.rer.nat. A. du Moulin INBIFO Institut filr biologische Forschung • K6Irt REPORT A o5oo/3o17.o9 RL53 (R) A16 PAGE 4-11 Date of receipt: 9.Jan.8o CR-number: CR-1766A Rel. mol~. mass: 162.23 (a) Source: Philip Morris Research Center Batch no.: - ~ Quantity: 1.o g Delivery container(s): ampul Description of test substance: clear colorl~ess liquid Storage:_ stored in exsiccator under nitrogen inside refrigerator Changes during storage (time from receipt of substance until its use): no changes noticed 0 INBIFO substance no.: S 2723 BI (a) Relative molecular mass of 162.23 rounded to the next W24 figure is 162.
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4 »KW„ PHILI~P MORRIS RxSF..4RCF{' CENTER (R,S) - 1-hiethyl-3-(3-pyridyl) pyrrolidine N3f' 73.;5 Yg:: T=: Sample # 7aR6-1413 u MP B? 1',10o/?. Number C H , , 8826 D: t,~ 611 79 ~^ ~Zt C3:1, 8P23 6/1;/79 JCoCI„ . # From Caicd. Found D,1te__ upaL'1. Sub,ai tter Approved_ Ecnp . Formula C 1oll'1,,112 . 1•1oI. Weight 162.23 1) Ln4, GrCKZCO'OE+-- 2) P,aPli , H'_ y CR-1766r ~ I 3) Ylali, C1iyI PI 4) 311 3 SoIL`.]_? it}`: ~T~C!n rn?ni, cnlvontc dilute acid Derivatives: Recrystallization, GC, TLC Data: at 10°/min)' Corr:nents :
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OTKMqO INBIFO Institut fur biologische Forschung • K61n REPORT A o500/3017.09 RL53 (R) A17 PAGE 4-13 Date of receipts U7.'_g.79 CR-number: CR-177oA Rel. mol. mass: 19o.28'(a). Source: Philip Morris Research Center Batch no.: - ~ Quantity: 5 ampuls with o.2 g each Delivery container(z): ampul Description of test substance: cLear colorless liquid Storage: stored in exsiccator under nitrogen inside refrigerator Changes during storage (time from receipt of substance until its use),: no changes noticed ® INBIFO substance no.: S 2724 Al to A5 (a) Relative mol~ecul~ar mass of 19o.28 rounded to the next W24 figure is 196.
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in this laboratory. (b) It is generally assume& that the sympathomimetic contractile effects of acetylcholine and L-nicotine on the thoracic aorta are indirect as on the pulmonary artery. REPORT A o500/3o17.o9 PHILIP TdORRZS RESERRCH CENTER New 0 . Known 0 PAGE 4-14 Emp. Formula C,,fi,aFl, Mol. Weight 190.23 lit. Ref. Na.me (R,S) - 5 - Ethylnicoti'ne STRUCTU.RE: bETHOD: OF PREP• 0 ti II )taCrrorf, O H + HCH -=r CR-1770 J3:.1L 7359 Pg;, 26 Soliubility: Connon organic solvents, Fanple # 7359-26-1 dilvte acid' :'_.D BP 100-110 °/0.=5 mn To be tested ior (amounts supplied) ; ® Numb er Da-e ~ RR 23372 2/'1 :~, J9 ~ IIV ~'- MV-t 8493 ' 2' 23J; 7! i 0rr,1, Derivatives: ~ E5 ' 8499 2.?.3/79 CDQ13 Uipicrate, m.p.. 184-1869 A nal. ii From (see CR-1770) tate Recrystallization; GC, TLC Data: Calcd. Foun d TLC, RF = 0.64 (CHC1,, C,HsOH, NH„ON - C H 85c14:1) ); Conunen ts : IIatc Submi ft!l!_>/'7,1 tter Project ~' 250i) _ Appro ved
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(a) Relative molecular mass of 148.2o rounded to the next W24 figure is 147. oTncw.V , INBIFOInstitutfifrbiolbgische Forschung • Kbin REPORT A o5oo/3o17.o9 RL53 (R) A18' PAGE 4-15 Date of receipt: 17.Aug.79 CR-number: CR-1772 Rel. mol. mass: 190.28 (a) Source: Philip Morris Research Center Batch no.: ® Quantity: 4 ampuls with o.2 g each Delivery container(s),: amLul Description of test substance: clear colorless liquid Storage: stored in exsiccator under nitrogen inside refrigerator Changes during storage (:time from receipt of su')stance until its use): no changes noticed 0 LNBIFO substance no.: 3 2726 Al to A4 (a) Reliative molecular mass of 19o.28 rounded to the next W24 figure is 196. j r ae,
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t; 13.90 18.73 Date 3/23/72 Subraitter Project ,~ Approved .7_ PHILIP MORRIS RESEARCii'CENTER' le # ' 7393-36 7393 P~, ~' 36 BP 66-750[,;.^1 rm Number DEce $t?'' °1t tiaC'i3n i 1 113 !{ + HCH i CR-1772 Solub;:ity: Co^m.cn organic solvents, Derivatives: . !1 From Recrystall!ization, GC, TLC Data: GC: RI = 2.5 min (5% SE-30, 2000) TLC:, RF = 0.64 (CHC1 3, EtOH, NK,0!f - 85:14 Emp. Formula C1zl1t0J2 I Mol. Weight 190.28 ~
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(a) Relative molecular mass of 176.26 rounded to the next W24 figure is 178. INBIFO Institut ftDr biologische Forschung - K(Sln REPORT A o5oo/3o17.o9 RL53 (R) AU9 PAGE 4-17 Date of receipt: 17.Aug.79 CR-number: CR-1773 Rel. mol. mass: 178.23 (a) Source: Philip Morris Research Center Batch no.: ® Quantity: o.9'g Delivery container(s): ampul Description of test substance:: firm orange colored substance Stora, : storediin exsiccator under nitrogen inside refrigerator - Changes during storage (time from receipt of substance until, its use): no changes noticed ® INBIFO substance no.: S 2727 A1 (a) ReLative molecular mass of 178.23 rounded to the next W24 figure is 178.
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PHILIP MDRRIS RESEA?:CII CENTE~t Lit. Ref. E. C. Taylor and Pl. E. Boyer, J. Org. •Chem., 24, 275 (1959) STRUCTURE': NBO' '_7277 P,,•," 182 Sample # 7277-1£;2z uven [:- MP B? nm Number Da_,. 5.~) * ant 8632 8633 3/30/79 Solubility: !Jater, Et'UH, _co,-.:^on orn,n: soluents Comments: [a]p, , -159.5 (c 2.52, Cll!.C1,)
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(a) Relative molecular mass of 176.25 rounded to the next W24 figure is 178. r INBIFO4nstitut furibiologische Forschur~ • KbIn : REPORT A o500/3o17.o9 RL53,'(R) A2o PAGE 4-19 4.2 Reference Substaxs:e r- 4.2.1 Nicotinehvdrog~n_(±)_tartrat --------- --- ---- Date of receipt: ~ 13.Feb 8o Label on del'ivery container: Nicc,: ini.ydrog-.:z-(+)-tartraE (a) 99 oj,~, _ar dip Biochemie C18H26N2012 2H.20 MG 498.44 (b) Batch no.: o5oo445 Quantity: 25 g Delivery container: grey plast'.c bottle with black screw cap Description of test substance: white powder Changes during storage (time from receipt of substance until its use): no changes noticed INBIFO substance no.: S 2738 A2 (a) This substance contains 2 tartrate residues per molecule. According to IUPAC it should' be named L-nicotine bis(hydrogen)- G-tartrate. (b) Relative molecular mass of 498.44 rounded to the next W24 figure is 511. .••«a~
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h y.i~ y.un Comments: Dace 51271T5 Submicter Project if'2aj Approve& INBIFO Instiiut fur biologische 'r'orschung • Wn REPORT A o5o0/3o17.o9 RL53 (R) A21 PAGE 4-20 4.2.2 Noradrenaline Date of receipt: Label on delivert container: Rel. mol. mass: February, 1979 Arterenol (a) 2o5 (b) 0 Source: Hoechst AG, D-6ooo Frankfurt Batch no.: - Quantity: Delivery container: 25 ampuls, 1 ml each (= 1 mg) glass ampuls Description of the test compound: Storage: cl~ear, col~orless solution stored in refrigerator ID Changes during the storage (time from the receipt of the substance until its use): INBIFO substance no.: o changes noticed (',a) Noradrenaline-HCL in physiological, saline (b) Relative mol'e-:ular mass of 205 rounded to the next W24 figure is 196 ..~.....s~
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(a) Relative molecular mass of 176.25 rounded to the next W24 figure is 178. y. KW&t INBIFO Institut titr biologische Forschung • K6In REPORT A o5oo/3o17.o9 RL53'(R) A22 PAGE 5-1 METHOD ® 5.1 Animals Species, strain: albino rabbit, New Zealand White Breeder: I. Gentz D-692o Sinsheim Microbiol~ogical conditions of breeding and.housing: conventional Sex: male (odd numbers) and female (even numbers)' Acclimatization period: .GT.7 days Body weight: approx. 3 to 4 kg 5.2 Animal Housing Animal room: INBIFQ:animal area C, room R21o Air: loo percent fresh air, delivered from a 5o m high suction tube, ~ approx. 15 changes/h filter: fine filter class C. Room temperature: 22 + 2 degrees centigrad'e (a) Rel. humidity: 55 + lo percent (a) (a) At outside temperatures above 28 degrees centigrade and at extremely high relative humidity, these specifications may nct always be maintained. I !fJ~IFn lhct~ha/ /i'ir MinlnnicrF.e Cn.enM .. +. v:a..
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N INBIFO Institut fUr biologische Forschung - K81n REPORT A o5oo/3o17.o9 RL53 (R) A23 PAGE 5-2 time cycle: LD 12 : 12, L o6.oo to 18.oo source: "daylight" fluorescent lamps, Universal Weiss, 4o and 65 W/25 Osram GmbH, D-8ooo Munchen 1' intensity in the cages: approx. 2o to loo Lux (a) stainless steel cages with wire grids, base area: 56 cm x 43 cm, height: 34 cm. Animals per cage: 5.3 Food and Drinking,Water Food: standard pellet diet for adult rabbits, Herilan Kan-Haltung, H. Eggersmann,KG, Kraftfutterwerk, D-326o Rinteln/Weser, see PAGE 5-3 Food supply: ad libitum Water: tap water ~ water suppl!y: ad libitum Test substances: dissolved in saline, stock solutions: 5.62x1oE-2 mol/l neutralized with concentrated HC1, storage at approx. -2o degrees centigrade Reference substances: daily fresh nicotine solution in saline, neutrallized with 1o N NaOH daily fresh noradrenaline solution in salline (a) higher intensity during handling of animals and cleaning of rooms
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(a) Relative molecuTar mass of 19o.28 rounded to the next W24 figure is 196. vu>rwr INBIFO Institut fur biologische Forschung • K81n REPORT A o5oo/3o1,7.o9 Abpackungen: 50-, 25-kg-Papiersacke oder Papiersacke mit~Polyaethyteneinlage Pressung: 3 mm, 4 mm, rund HERILAN KAN-HALTUNG Alleinfutter fiir die Haltung ausgewachsener Kaninchen Energiegehalt: 8 500 joule umsetzbare Energie / kg Fertigfutter. 0 Gc half an Rohnahrstotfen: (% d'er lulttrockenen Substanz), C Rohprotein 14 Rohfett 2 Rohfaser 14 PAGE 5-3 Gehalt an Mineralien und Spurenelementen: (%der lufttrockenen g/kg Fertigfutter Substanz) Ca 1.0 Fe mm.0,15 P 0,8 Mn min.0;08 Na 0,25 Cu min.0,02 K 1,3 Zn min.0,05 Mg 0,4 Vitaminzusatz pro kg Fertigfutter Durchschnittlioher Gehalt an,Aminosauren: Normalfutter Fortified-Futter (Angaben in g AS / kg Futter) Vitamin A 10 000 I. E. 20 000 I. E. Alanin 2,4 Vitamin D3 400 I. E. 600 I. E. Arginin 18,8 Vitamin E 150 mg 200 mg Asparaginsaure 3.5 Vitamin K3 10mg 15mg Cystin '?,1. Vitamin C 100mg 150mg Gluteminsaure .0 1, Vitamin B, 20mg 30mg Glycim 17.4 Vitamin BZ. 30mg 60mg Histidin 8.3 Vitamin B6. 20mg 30 mg Iso-Leucin 13.9 Vitamin B,, 30~mcg 40 mcg Leucin 25A . Ca-Pantothenat' 40'mg 60 mg. Lysin. 5,8 Nikotinsaureamid 40 mg 60 mg Methionin 2,8 Cholinchiorid 1 000'mg 1 200 mg. Phenylalanin 3.6 Fotsaure 5mg 6mg, Prolin 3:8 Inosit 5 mg 10 mg. Serin 2,4' Biotin 801mcg 100 mcg Threonin 13;2 Tryptophan 5~3 Tyrosin 18:7 Valin 19.3 71MV.At
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.~J S u b m itter 1!i%r, Z'.;!~ " "~_' , Approved_ lY. . . ~...c,+ ~. INBIFO Institut fur t3iologische Forschung • Kbin REPORT A o5oo/3o17.o9 RL53 (R) A24 5.5 Preparation of the Aortic Stri~ps Principle: - PAGE 5-4 Time: immediately after exsanguination of the rabbit Material and quantity: 1 rabbit ® Equipment: dissection instruments, nylon thread, 4 water jacketed glass vessels (2o ml) with stopcock for flushing and frit for aeration, 2 immersion thermostats, L-shaped glass rods Chemicals and reagents: sodium chle:ride, Mr 58.4 (a) potassium chloride, MR 74.6 calcium chlorid 2-hydrate, Mr 147.0 magnesium chloride 6-hydrace, Mr 2o3.3 sodium hydrogen carbonate, Mr 84.0 primary sodium phosphate 1-hydrate, Mr 138.o disodium ethylenediaminetetraacetic acid 2-hyd rate, Mr 372.o, E. Merck, D-6ioo Darmstadt
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(a) Relative molecular mass of 162.23 rounded' to the next h'24 figure is 162. IfVBIFO Institut fi)r biologische Forschung • KBIn REPORT A o5oo/3o17.o9 RL53 (R) A25 PAGE 5-5 Tyrode"s solution: 136.9 mmol/1 (8.o g/1) sodium chloridP 2.68 mmol/1 (o.2 g/1) potassium chloride 1.8 mmol/1 (o.26S g/1) cal~cium chloride 2-hydrate t.o mmol/1 (o.213 g/1) magnesium chloride 6-hydrate 11.9 mmol/1 (1.o g/1) sodium hydrogen carbonate o.41 mmol/1 (o.o57 g/1) primary sodium phosphate 1-hydrate 5.5 mmol/1 (1.1 g/1) glucose i-hydrate o.o27 mmol/1 (0.01 g/1) disodium ethylenediaminetetraacetic acid (EDTA) The solution is prepared from the following stock solutions: stock solution I sodium chloride 20o g potassium chloride 5 g calcium chloride 1-hydrate 6.6 g magnesium chloride 6-hydrate 5.33 g distilled water to looo ml stock solution II sodium hydrog,en carbonate 5o g distilliediwater to iooo mi, stock solution III primary sodium phosphate 1-hydrate 2.87 g distilled water to 50o m! To avo+4preci'pitation of carbonates andiphosphates, the distilled water must be stirred well when adding the stoc}: solutions in the order given be l o++.
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Dace f;ll S/'IT Sub-aitter_ Approved I INBIFO Institut filr biologische Forschung •Koin REPORT A o5oo/3o17.o9 RL53 (R) A26 PAGE 5-6 stock solution I 4o ml stock solution II 2o ml stock solution III to ml glucose 1-hydrate 1.1 g EDTA 0.01 g distilled water to looo ml aeration with carbogen, a mixture of'95 0/0 02 and 5 0/o C02 pH 7.5 (approx.) A rabbit was killed by a blow on the neck. The animal was exsan- guinated by cutting the carotid arteries. The descending thoracic aorta was removed and transferred: to a dish containing Tyrode's solution (pH 7.4, 37 degrees centigrade). Adipose tissue and coagulated blood were trimmedi off. 4 pieces of the aorta were cut helically into strips, about 4 mm wide and 3o to 4o mm long,. Threads were attached to both. ends of the strips. One end of each strip was fastened to a glass rod. Then the strips were hung into the individual organ bath, containing Tyrode's soLu- tion at 37 deqrees centigrade aerated with a mixture of oxygen (95 percent) and carbon dioxide (5 percent). The remaining thread was attached to the 4th hole of the long armlof the lever.
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(a) Relative molecular mass of 19o.28 rounded to the next W24 figure is 196. »."I INBIFO Institut (ur biologische Forschung • K01n REPORT A o500/3o17.o9 RL53 (R) A27 5.6 Execution of the Experiment a 0 Principle: Time: Material and quantity: Results expressed in: Equipment: PAGE 5-7 The longitudinal isotonic contraction is measured by means of an induction coil and transferred to a recorder. The amplitude on the recorder is --oportional to the contraction of e muscle. after preparation of the aortic strips at least 4 aortic strips umol/1 4 water jacketed glass vessels (2o ml) with stopcock for flushing and frit for aeration (G3) 2 immersion thermostats 2 glass storage vessels for Tyrode's solution each 2 1 4 two armed Levers, Hugo Sachs Electronic, D-78o1 Hug!stetten 4 hf-modems for power supply to the induction coil, Hugo Sachs Electronic, D-78oi Hugstetten 2 two channel recorders, Servogor, Metrawatt GmbH, D-85oo Nurnberg Chemicals and reagents: Tyrode's solution (same as given in 5.5 Preparation of the Aortic Strips) Carbogen test and reference substances 37 .v.B
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INBIFO Institut tur biologische Forschung • Kbtn REPORT A o500/301'7.09 RL53 (R) A2d Procedure: PAGE 5-8 (1) Calibration (see FIGURE A) The calibration of the lever, hf-modem and the recorder was carried out before each experi- ment. To obtain a preload of 3 g on the short arm of the lever, recorder. an ampl'itude of 1oo mm on the is + 1o mm. lo mm correspond to arm. Maximum travel of the long arm of the lever, i. e. the arm to which the strip was connected, placing the weight on the short a 3 g weight attached to the 4th hole of the long arm was counterbalanced by appropriately (2) Experiment Preliminary experiments revealed that the sensitivity of rabbit aortic strips to noradrenaline or nicotine increases with the number of appl,ications. For reason of standardization before each application of the reference substance or a test subutance a noradrenalline contraction was induced ("internal standard"). Test cycle: The aortic strip was allowed to equilibrate for 2 hours (step no. 1 of TABLE A). During this period the organ bath solution was replaced severall times with fresh Tyrode's solution. After the equillibra- tion period the aortic strip was exposed to 1.ooxloE-7 mol/l noradrenaline for 5 min (step no. 2). Then the organ bath solution was changed 4 times at intervals of 5 min (step no. 3).
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(a) Relative molecular mass of 19o.28 rounded to the next W24 figure is 196. »nwu ® REPORT A o5oo/3o17.o9 RL21 (R) B8 M PAGE 5-9 elangation 1 2 3 4 5 6 7 8 9 10mm hote no. 1 2 3 4 5 6 7 8 9 0 0 0 U FIGURE A LEVER (a)! In this example the organ is attached to the 8th hole and not, as mentioned in the text (see 5.6) to the 4th hole.
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Da te 8/1 5/79 Submi t ter Approved_ Comments: INBIFO Institut fur biologische Forschung • K6In REPORT A o5oo/3o17.o9 RL53 (R) A29 PAGE 5-l0 Thereafter the strip was allowed to equilibrate for another 5 min (step no. 4). Then L-nicotine bis(hydrogen)-L-tartrate was added to give a final concentration in organ bath of 3.16x1oE-4 mol/1 (step no. 5). This concentra- tion evoked the maximum nicotine contraction (a). (a) The maximum nicotine contraction by definition is the con- traction elicited by 316 micromol/l nicotine (= reference substance). The concentration-response curve for the reference substance, included in this report, shows that this concentration did elicit the maximum nicotinA contraction (see TABLE 4.1o and FIGURE 7).
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(a) Relative molecular mass of 178.23 rounded to the next W24 figure is 178. ]7RYYfI ~.. INBIFO Institut (ur biologische Forschung • KUIn REPORT A o5oo/3o1,7.o9 RL53 (R) A3o PAGE 5-11 STEP TIME SPECIFIED INCUBATION' NUMBER (min) CONDITIONES 1 o to 12o equilibration period 2 12o addition of'2oo ul noradrenaline (a) 3 125 to 140 4 times washing 4 14o to 145 equilibration period 5 145 addition of 2oo ul L-nicotine bis (hydrogen)-L-tartrate (reference substance) (b) 6 15o to 165 4 times washing ® 7 165 to 17o equilibration period 8 17o addition of 2oo u1 noradrenaline (a) 9 175 to 190 4 times washing 1~0 19o to 195 equilibration period 11 195 addition of the test substance (c) 1:2 2oo to 215 4 times washing 113 215 to 22o equilibration period 1i4 22o additiDn of 2oo u1 noradrenaline (a) 1!5 225 to 24o 4 times washing 16 24o to 245 equilibration period 13 245 addition of the test substance (c) 18 25o to 265 4 times washing 19 265 to 27o equilibration period' 2o 27o addition of 2oo ul noradrenaline (a) 21 275 to 290 4 times washing 22 29o to 295 equilibration period' 23 295 addition of the test substance (c) 24 3oo to 315 4 times washing ~ 25 315 to 32o equilibration period 26 32o addition of 2oo ul noradrenaline (a) 27 325 to 34o 4 times washing 28 34o to 345 equilibration period 29 345 addition of 2oo u1 L-nicotine bis (hydrogen)-L-tartrate (reference substance) (b) TABLE A TEST CYCLE (a) noradrenaline concentration: 1'.ooxloE-5 mol/l, final concen- tration in organ bath:l.ooxloE-7 mol/1 (b) L-nicotine bis(hydrogen)-L-tartrate concentration: 3.16x1oE-2 mol/1, final concentration in organ bath: 3. 1 6x 1'oE-4 moll/1 (c)i different concentrations of the test substance are applied in steps 11, 17 andi23
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Date 8/i5/19' Submitter Approvcd_ Comnents: [a]~~,s -159i.5 (c 2.52, M:C INBIFO~Institut fur biolbgische Forschung • Kbin REPORT A o500/3017.09 RL53 (R) B3 SZ PAGE 5-1!2 5.7 Gas Chromatographic Determination of Purity of "SYNTHETIC COMPOUNDS" Compound: GC of diluted solution with two GC-columns with differ- ent polarity integration of peak areas and calculation of substance composition CR-1316A, -1408, -1523 Material and quantity: 1io ul substance diluted Equipment: with 4o ul dichloromethane, approx. 1 ull gas chromatograph: HP 573o A, detector: FID, laboratory data system: HP 3351 A, Hewlett-Packard GmbH, D-6ooo Frankfurt/Main recorder: Servogor 21o, Metrawatt GmbH:, D-85oo Nurnberg Chemicals and reagents: dichloromethane, No. 822271, E. Merck, D-61oo Darmstadt 1 Gas chromatography Stationary phase: Column: non-polar, Apiezon D 2 m x 1/8 inch outer diameter, stainless steel Column pack'_'ng: 10 o/o Apiezon L and lo o/o KOH on Chromosorb W-AW DMCS, 8o to 1oo mesh
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(a) This substance contains 2 tartrate residues per molecul~e. According to IUPAC it should be named L-nicotine bis(hydrogen)- L-tartrate. (b) Relative molecular mass of 498.44 rounded to the next W24'figure is 511. INBIFO Institut fur biologische Forschung • KBIn REPORT A oSoo/3o17.o9 RL53 (R) B4 SZ PAGE 5-13 Carrier gas and flow rate: nitrogen, 3o ml/min Oven temperature: temperature program: 13o to 21o degress centi- grade, rate 2 degrees centi- grade/min, 8 min 21o degress centigrade Injection port temperature: 23o degrees centigrade ® Detector temperature: 25o degrees centigrade Stationary phase: polar, Carbowax 2oM Column: 2 m x 1/8 inch outer diameter, stainless steel Column packing: 15 0/o Carbowax 2oM and 10 o/o KOH on Chromosorb W-AW DMCS, 8o to loo mesh Carrier gas and flow rate: nitrogen, 3o ml/min. Oven temperature: temperature program: 11o to 2oo degrees centi- grade, rate 2 degrees ~ centigrade/min, 8'min 2oo degrees centigrade Injection port temperature: 23o degrees centigrade Detector temperature: 25o degrees centigrade ,-.v„
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(a) Noradrenaline-HCL in physiological saline (b) Relative mo?ecular mass of 2o5 rounded to the next W24 figure is 1!96 »xwe, INBIFO Institut fur biologische Forschung • KtSIn REPORT A o500/3o1'.7.o9 RL53 (R) B5 PAGE 5-14 5.8 Thin Layer Chromatographic Determination of Purity of "SYNTyETIC COMPOUNDS" Principle: Compound: 0 separation of compounds by their different adsorption to the sta- tionary phase CR-1316A, -14o8, -1523 Material and quantity: 1 ul of diluted substance (1o ul substance plus 4o ul dichloromethane) Equipment: TLC plates Silica gel, 6o F 254, E. Merck, D-61oo Darmstadt Universal UV 254 mm, 366 mm, Camac, D-looo Berlin glass development tank, Desaga, D-6'.loo He idel~berg Chemicals and reagents: dichloromethane, . ethanol, absolute, chloroform, ® aquous ammonia, E. Merck, D-61oo Darmstadt Procedure: application of 1 ul diluted substance 2 cm from lower border of the plate development system: chloroform : ethanol : aq. ammonia = 84 : 15 : 1 dvvellopment time: approx. 55 min. location of spots: UV 254 nm
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('a) At outside temperatures above 28 degrees centigraoe ana ac extremely high relative humidity, these specifications may nct always be maintained. INBIFO Institut~fur biologische Forschung • Ktlln. REPORT A oSoo/3o17.o9 RL53 (R) B1 PAGE 6-1' EVALUATION'. aa~3~aasa=~ Contraction activity: With each aortic strip the contractions elicited by 2 applications of L-nicotine bis(hydrogen)-L-tartrate (steps no. 5 and 29 of TABLES A and 3) are calcullated relative to the respective preceding contraction elicited by noradrenaline (steps no. 2 and 26). The mean of the 2 nicotine values is the maximum nicotine amplitude, which is ~ taken as loo percent (see footnote on PAGE 5-10). The amplitudes elicited by the test substances are first calculated relative to the respective preceding r.oradrenaline amplitudes and are cinally given as percentages of the maximum nicotine amplitude. 37K" I ® For calculation of the effective concentration of a test substance, the responses of at ].east 3 aortic strips to at least 3 different concentrations for each strip were used (FIGURES 1 to 7). For regzession analysis a log concentration-linear response plot was applied. Ratio of effective concentrations: effective concentration reference substance divided by effective concentration test substance J.T El
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(a) higher i!ntensity during handl,ing of animals and cleaning of rooms :ruw„ INBIFO Institut fur biologische Forschung • K81n REPORT A o5oo/3o17.o9 RL53 (,R) B12 PAGE 7-1/8r1 7 STORAGE OF MATERIALS AND RECORDS Remaining quantities of test substances will be used for other test models or are stored. Records are stored in our archives for at least 5 years. They can be claimed by the client. 8 RESULTS 0 8.1 Text text see SUMMARY 0 37 Kwe+
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CCMP. OoNFRACf ION (0/0) (a) EFFECTIVE RATIO OF OCA1C. (b) EFFEJCPIVE C(NCE:NFRATICN COW. (tanol/1) (tsnol/1) (ref. sub. ) (test sub.) CR- 3.16 5.62 1o.o 17.8 31.6 14o8 - - -. - - 1523 - -. - - 9.8 1652 5.1 21.8 32.2 68.9 83.1 177oA - -. - - 2.6 1772 -. - 5.3 28.4 58.4 1316A - - - - 0 1773 - - - - - 1274 - - - - 19.5 1766A - - - - o.58 ref. sub. - -- 6.5 37.2 58.4 TABLE 2 56.2 100 178 316 562 1000 178o 316o 0 - 0 - 0 - - -. - - 32.4 26.8 3o.8 35.2 30.9 - - - - - 78.5 - - - - - - - 12.1 (c) 2.37 9.0 15.4 36.7 39.1 38.5 - - - - - 75.7 81.5 83.3 78.7 80.7 - - - 34.8 (d) o.825 0 0 0 0 0 - - - - - -. - 0 0 0 - - - - - 41.1 68.o 63.7 72.2 78.9 - - - 90.9 o.316 6.5 47.7 4o,o 63.2 91.0 - - - 178.o 0.162 So.9 90.1 98.7 loo 96.7 90.4 76.9 64.9 28.7 (d) (1.00) E.'ONI'FACTION (0/0), EFFECTIVE CCNCENPRATICN AND RATIO OF EFFECTIVE CQ4CEN-PRATIGN (a) mean contraction froT TABLES 4.1 to 4.1o (b) the effective concentration of a substance is defined as that molar concentration which evokes So % of the maxim.m nicotine_ contraction (c,d) the values fr-crn 3.16 to 31.6 and fran lo.o to 178 umol/l respectively were used for calculation V9zsESZOOT ®
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STEP NUMBER ORGAN BATH CONCENTRATION AMPLITUDE ACCORDING TO TABLE A NORADRE- REF. TEST ABS. RELATIVE TO NALINE SUBST. SUBST. PRECEDING MAXIMUM NORADRENALINE NICOTINE AMPLITUDE AMPLITUDE (umol/1) (umol/1) (umol/1) (mm) (o/o) (0/0) 2 0.1 -. - 78 - - 5 - 316 - 79 lol.3 - 8 0.1 - - 111 - - 11 - - 56.2 0 0 0 14 0.1 - - 126 - - 17 - - 178 0 0 0 2o 0.1 - - 12o - -. 23 - - 562 0 0 0 26 0.1 - - 128 -. - 29 - 316 - 1o4 81.3 - 5, 29 MEAN - - - - 91.3 (a) TABLE 3.1.1 AMPLITUDE ON THE RECORDER, CR-14o8 rabbit no. 1314, 2nd str:n (a) This value is set as a loo (o/o) nicotine contraction (maximum nicotine amplitude). I V9%sCs%ooT
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STEP NUMBER CORDING ORGAN BATH CONCENTRATION TO AC TABLE A NORADRE- REF. TEST NALINE SUBST. SUBST. (umol/1) (umol/1) (umol/1) 316 56.2 - - - 178 - - - 562 - - 316 - TABLE 3.1.3 AMPLITUDE ON THE RECORDER, CR-14o8 rabbit no. 1479, 2nd strip AMPLITUDE ABS. mm) RELATIVE TO PRECEDING MAXIMUM NORADRENALINE NICOTINE AMPLITUDE AMPLITUDE (0/0) (0/0) 73 - - 78 1o6.8 - 96 - 0 0 0 12o - - 0 0 0 127 - - 0 0 0 138 - - 122 88.4 - 97.6 (a) (a) This value is set as a 100-0/o nicotine contraction (maximum nicotine amplitude). !39Z6E6z00Z
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REPORT A o500/3017.09 RL21 (R) A8 (GD) c STEP NUMBER ORGAN PATH CONCENTRATION AMPLITUDE ACCORDING TABLE A TO NORADRE- REF. TEST ABS. RELATIVE TO ET O 0 NALINE SUBST. SUBST. PRECEDING MAXIMUM cn NORADRENALINE NICOTINE ~ 0 AMPLITUDE AMPLITUDE =r CD 'T1 (umol/1) (umol/1) (umol/1) (mm) (0/0) (0/0) 0 ~ i c ~ 2 0.1 123 c ~ 5 - 316 135 109.8 - U2 8 0.1 149 11 - 562 28 18.8 19.7 a 14 0.1 167 ~ 17 - 316 39 23.4 24.5 2o 0.1 182 23 - 178 45 24.7 25.9 26 0.1 190 29 - 316 154 81.1 5, 29 MEAN 95.5 (a) TABLE 3.2.1 AMPLITUDE ON THE RECORDER, CR-1523 rabbit no. 1292, 2nd strip (a) This value is set as a loo-o/o nicotine contraction (maximum nicotine amplitude). 99ZsEszooT
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REPORT A o500/3017.09 RL21 (R) A9 (GD) STEP NUMBER ORGAN BATH CONCENTRATION AMPLITUDE ACCORDING TO TABLE A NORADRE- REF. TEST ABS. RELATIVE TO NALINE SUBST._ SUBST. PRECEDING MAXIMUM NORADRENALINE NICOTINE AMPLITUDE AMPLITUDE (umol/1) (umol/1) (umol/1) (mm) (0/0) (0/0) 2 0.1 - - 111 - - 5 - 316 - 142 127.9 - 8 0.1 - - 136 - - 11 - - loo 36 26.5 25.7 14 0.1 - - 155 - - 17 - - 56.2 53 34.2 33.2 2o 0.1 -. - 163 - - 23 -. - 31.6 19 11.7 18.4 26 0.1 - - 17o - - 29 - 316 - 133 78.2 - 5, 29 MEAN - - - - 1o3.1 (a) TABLE 3.2.2 AMPLITUDE ON THE RECORDER, CR-1523 rabbit no. 1292, 4th strip (a) This value is set as a 100-0/o nicotine contraction (maximum nicotine amplitude). a :3 i 49zsCszooT
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0 REPORT A o5oo/3o17.o9 RL21 (R) Alo (GD) STEP NUMBER ORGAN BATH ACCORDING TO TABLE A NORADRE- NALINE (umol/1) 2 0.1 5 - 8 0.1 11 - 14 0.1 17 - 2 o 0.1 23 - 26 0.1 29 - , 29 MEAN - TABLE 3.2.3 AMPLITUDE ON THE RECORDER, rabbit no. 1298, 1st strip (a) This value is set as a CONCENTRATION AMPLITUDE REF. SUBST. TEST SUBST. ABS. RELATIVE TO PRECEDING NORADRENALINE AMPLITUDE MAXIMUM NICOTINE AMPLITUDE (umol/1) (umol/1) (mm) (0/0) (0/0) - - 1o4 - - 316 - 113 1o8.7 - - - 124 - - - 178 42 33.9 35.1 -. - 139 - - - 316 53 38.1 39.5 -. - 15o - - - 562 54 36.o 37.3 - - 150 - - 316 - 126 84.o - - - - 96.4 (a) CR-1523 loo-o/o nicotine cont raction (maximum nicotine amplitude). 8sMCszooi
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REPORT A o5oo/3a17.o9 RL21 (R) All (GD) STEP NUMBER ORGAN BATH CONCENTRATION AMPLITUDE ACCORDING TO TABLE A NORADRE- REF. TEST ABS. RELATIVE TO NALINE SUBST. SUBST. PRECEDING MAXIMUM NORADRENALINE NICOTINE AMPLITUDE AMPLITUDE (umol/1) (umol/1) (umol/1) (mm) (0/0) (0/0) 5, 29 MEAN TABLE 3.2.4 AMPLITUDE ON THE RECORDER, CR-1523 rabbit no. 1298, 3rd strip 83.6 (a) (a) This value is set as a 100-0/o nicotine contraction (maximum nicotine amplitude). a =1 --nnm NoM c fD :3 M Q fD n (D Ul (D •1 R Ha ru a rr 0 a ~nnn ~a m ro M K r y v s. O c • 7 U H O 0, ,r M r- a a ao 0 :1 0 0 r+ n h7 r• tD r~n r~7 L1r-? rt Crrn n :v r a t*m r* c rr :r LL r- v (D iD 0 aa ar•n x3 to r• N c ~~ Br•7 N fA O N r•rt n ro n 018 c R ~S r-rt < 7 RtD M O ta O O ~•R a O cT E t* a(n:7 a M n ,r R7 r• a O rt O ~ a Ul 0 122 - - 316 123 100.8 - . - 141 - - - 31.6 2 1.4 1.7 - - 154 - - - 56.2 43 27.9 33.4 - 163 - - - loo 40 24.5 29.3 - 211 - - 316 - 14o 66.4 - 69z6Us%ooZ
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REPORT A o5oo/3 o17.o9 RL21 (R) A12 (GD) STEP NUMBER ORGAN BATH CONCENTRATION AMPLITUDE ACCORDING TO TABLE A NORADRE- REF. TEST ABS. RELATIVE TO NALINE SUBST. SUBST. PRECEDING MAXIMUM NORADRENALINE NICOTINE AMPLITUDE AMPLITUDE (umol/1) (umol/1) (umol/1) (mm) (0/0) (0/0) 2 0.1 - - 81 - - 5 - 316 - 89 109.9 - 8 0.1 - - 101 - - 11 - - 31.6 15 14.9 19.0 14 0.1 - - 113 - - 17 - - 56.2 52 46.1 58.8 2o 0.1 - - 12o -. - 23 -. - loo 4o 33.3 42.5 26 0.1 - - 139 - - 29 - 316 - 65 46.8 - 5, 29 MEAN - - - - 78.4 (a) TABLE 3.2.5 AMPLITUDE ON THE RECORDER, CR-1523 rabbit no. 1475, 2nd strip (a) This value is set as a loo-o/o nicotine contraction (maximum nicotine amplitude). o4zsC6Zoot z M i rn s z u U v ~ .•. ..•. ~ O N a W W k ,t r. . . 1 7 (D rn + ~ 7 ~ 'O rn O, m r• - fn (D X X n C '•t ~ r O ~ rD O O r* - a W 4*7 r. 0 vO 3 3 Q ® 0 7 O O r• Ip N n f- r N ~ r* r• O r• 7 .O C~) 0 r 7 N :r 6 n 1 ~ 0 o r c~ M 7 1 n r. fR (D G 7 a n 71 ® a o Rr?
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0 REPORT A o5oo/3o17.09 RL21 (R) A13 (GD) STEP NUMBER ORGAN BATH CONCENTRATION AMPLITUDE ACCORDING TO TABLE A NORADRE- REF. TEST ABS. NALINE SUBST. SUBST. (umol/1) (umol/1) (umol/1) (mm) 2 5 8 11 14 17 2o 23 26 29 5, 29 MEAN 0.1 0.1 0.1 0.1 TABLE 3.2.6 AMPLITUDE ON THE RECORDER, CR-1523 rabbit no. 1475, 4th strip 25.3 3o.9 32.1 39.1 23.1 28.2 59.2 - 82.o (a) (a) This value is set as a 100-0/o nicotine contraction (maximum nicotine amplitude). 62 RELATIVE TO PRECEDING MAXIi4UM NORADRENALINE NICOTINE AMPLITUDE AMPLITUDE (0/0) (o/o) 1o4.8 316 - 65 - - 75 - 178 19 - - 84 - 316 27 - 91 - 562 21 - - 98 316 - 58 T~,~6C6~00T
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REPORT A oSoo/3o17.o9 RL21 (R) A14 (GD) STEP NUMBER ORGAN BATH CONCENTRATION AMPLITUDE ACCORDIVG TO TABLE A NORADRE- REF. TEST ABS. RELATIVE TO NALINE SUBST. SUBST. PRECEDING MAXIMUM NORADRENALINE NICOTINE AMPLITUDE AMPLITUDE (umol/1) (umol/1) (umol/1) (mm) (0/0) (0/0) 2 0.1 - - 90 - - 5 -. 316 - 105 116.7 - 8 0.1 - -. 1o7 - - 11 - - 178 37 34.6 31.1 14 0.1 - - 115 - -. 17 - - 316 48 41.7 37.5 2o 0.1 - - 122 - - 23 - - 562 52 42.6 38.3 26 0.1 - - 124 - - 29 -. 316 -- 131 1o5.6 - 5, 29 MEAN - - - - 111.2 (a) TABLE 3.2.7 AMPLITUDE ON THE RECORDER, CR-1523 rabbit no. 1316, 2nd strip (a) This value is set as a 100-0/o nicotine contraction (maximum nicotine amplitude). z~.zseG~ooi I,'
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REPORT A o500/3017.09 RL21 (R) A15 (GD) STEP NUMBER RD G O ORGAN BATH CONCENTRATION AMPLITUDE IN T ACCO TABLE A NORADRE- REF. TEST ABS. RELATIVE TO NALINE SUBST. SUBST. PRECEDING MAXIMUM NORADRENALINE_ NICOTINE AMPLITUDE AMPLITUDE (umol/1) (umol/3) (umol/1) (mm) (0/0) (0/0) 2 5 8 11 14 17 2o 23 ?6 5, 9 AN 0.1 0.1 v. 1 0.1 0.1 316 - - - - - - - 316 - -. 31.6 - 56.2 - 1oo - - 94 84 110 0 115 4 12o 10 123 101 - 89.4 - 0 - 3.5 - 8.3 - 82.1 85.8 (a) - -. 0 - 4.1 - 9.7 - - TABLE 3.2.8 AMPLITUDE ON THE RECORDER, CP -1523 rabbit no. 1316, 4th strip (a) This value is set as a loo-o/o nicotine contraction (maximum nicotine amplitude). C4G0GG40QT
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~ REPORT A o500/3o17.o9 RL17 (R) B24 STEP NUMBER ORGAN BATH CONCENTRATION AMPLITUDE ACCORDING TO TABLE A NORADRE- REF. TEST ABS. RELATIVE TO NALINE SUBST. SUBST. PRECEDING MAXIMUM NORADRENAL_INE NICOTINE _ AMPLITUDE AMPLITUDE (umol/1) (umol/1) (umol/1) (mm) (0/0) (0/0) 2 0.1 - 154 5 - 316 - 195 126.6 8 0._1 - - 156 1 1 -. - 31.6 173 110.9 87.6 14 0.1 - - 168 17 - - 17.8 126 75.o 59.2 2o 0.1 - - 172 - - 23 - - 10.0 88 51.2 4o.4 26 0.1 - - .GT.2oo 29 - 316 - .GT.2oo 5 126.6 (a) TABLE 3.3.1 AMPLITUDE ON THE RECORDER, CR-1652 rabbit no. 1274, 1st strip (a) This value is set as a loo-o/o nicotine contraction (maximum nicotine amplitude). V4%V(.GC.UVT
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® 0 REPORT A o5oo/3o17.o9 RL17 (R) B25 STEP NUMBER ORGAN BATH CONCENTRATION AMPLITUDE ACCORDING TO TABLE A NORADRE- REF. TEST ABS. RELATIVE TO NALINE SUBST. SUBST. PRECEDING MAXIMUM NORADRENALINE NICOTINE AMPLITUDE AMPLITUDE: (umol/1) (umol/1) (umol/1) (mm) (0/0) (o/o) 2 5 8 11 14 17 2o 23 26 29 5, 9 AN 0.1 - 0.1 - 0.1 - 0.1 - 0.1 - - - 316 - - - - - - - 316 - - - - 178.0 - 100.0 - 56.2 - - - 13o 167 160 156 149 144 157 144 156 196 - - 128.5 - 97.5 - 96.6 - 91.7 - 125.6 127.1 ) - - - 76.7 - 76.0 -. 72.1 - - TABLE 3.3.2 AMPLITUDE ON THE RECORDER, CR-1652 rabbit no. 1274, 2nd c:trip (a) This value is set as a loo-o/o nicotine contraction (maximum nicotine amplitude). SF..GV(.p4UUT
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REPORT A o5oo/3o17.o9 RL17 (R) B26 STEP NUMBER CCORDING TO ORGAN BATH CONCENTRATION AMPLITUDE A TABLE_ A NORADRE- NALINE (umol/1) REF. SUBST. (umol/1) TEST SUBST. (umol/1) ABS. mm) RELATIVE TO PRECEDING NORADRENALINE AMPLITUDE (0/0) MAXIMUM NICOTINE AMPLI'PUDE (0/0) 2 0.1 - - 119 - _ 5 - 316 - 136 114.3 - 8 0.1 - - 13o - - 11 - - 3.16 23 17.7 15.2 14 0.1 -. - 137 - - 17 - - 5.62 61 44.5 38.2 2o 0.1 - - 149 - - 23 - - 10.0 5o 33.6 28.8 26 0.1 - - 148 - - 29 - 316 - 176 118.9 - 5, 29 MEAN - - - - 116.6 (a) TABLE 3.3.3 AMPLITUDE ON THE RECORDER, CR-1652 rabbit no. I2~5, 1st strip (a) This value is set as a loo-o/o nicotine contraction (maximum nicotine amplitude). 9~~6~6400T
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®. ® REPORT A o500/3017.09 RL17 (R) B27 z 0) ~ 3 N G C STEP NUMBER ORGAN BATH CONCENTRATIc3'i AMPLITUDE ~ \r :ORDING TO 0 'I.+BLE A NORADRE- REF. TEST ABS. RELATIVE TO 0 NALINE SUBST. SUBST. PRECEDING NORADRENALINE MAXIMUM NICOTINE <_n ~i. ~ AMPLITUDE AMPLITUDE ~ (umol/1) (umol/1) (umol/1) (mm) (o/o) (0/0) 0 A ~ 2 0.1 - 126 - - C ~ 5 - 316 - 125 99.2 - 8 0.1 - - 147 - - 11 - - 17.8 115 78.2 83 5 ~ 14 0.1 - - 151 - . - oi 0 17 - - 31.6 1o5 69.5 74.2 2o 0.1 - - 156 - -. 23 - - 56.2 97 62.2 66.4 26 0.1 - - 152 - -- 29 - 316 - 134 88.2 - 5, 29 ME AN - - - - 93.7 (a) TABLE 3.3. 4 AMPLITUDE ON THE RECORDER, CR-1652 rabbit no. 1265, 2nd strip (a) This value is se` as a 100-0/o nicotine contraction (maximum nicotine amplitude). i 44Z6C5~ 00T I i j
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STEP NUMBER ORGAN BATH CONCENTRATION AMPLITUDE ACCORDING TO TABLE A NORADRE- NALINE (umol/1) REF. SUBST. (umol/1) TEST SUBST. (umol/1) ABS. mm) RELATIVE TO PRECEDING NORADRENALINE AMPLITUDE (o/o) MAXIMUM NICOTINE AMPLITUDE (0/0) 0.1 99 5 316 - 98 99.0 - 8 0.1 118 11 3.16 4 3.4 3.3 14 0.1 125 17 5.62 26 2o.8 2o.4 20 0.1 137 23 - 10.0 24 17.5 17.2 26 0.1 - . 140 29 316 - 147 105.0 5, 29 MEAN - - - - 1o2.o (a) TABLE 3.3.5 AMPLITUDE ON THE RECORDER, CR-1652 rabbit no. 1266, 3rd strip (a) This value is set as a loo-o/o nicotine contraction (maximum nicotine amplitude). 8~.%6C6~00T TABLE AMPLI7 rabbi i (a) Tt
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® REPORT A o5oo/3oi7.o9 RL17 (R) B29 Y RE PORT 2 1 W - T O :3 N . C STEP NUMBER ORGAN BAT H CONC~LiTRATION AMPLITUDE I ~. STEP N ACCORD ACCORDING TO Q O TABLE TABLE A NORADRE- REF. TEST ABS. RELATIVE TO 0 _ NALINE SUB3T SUBST. PRECEDING MAXIMUM c0 . - N NORADRENALINE AMPLITUDE NICOTINE AMPLITUDE h =r m ~ (umol/1) (umol/1) (umol/1) (mm) (0/0) (0/0) 0 ~ 0 2 0.1 - - 148 - - ::r c ~ 2 5 5 - 316 - 145 98.0 - <n 8 8 0.1 - - 169 - - 11 11 14 - 0.1 - - 17.8 - 94 176 55.6 - 54.6 - ;K o: 3 14 17 17 - - 31.6 133 75.6 74.3 2o 2o 0.1 - - 184 - - - - 23 23 - -. 56.2 14o 76.1 74.8 26 26 0.1 - - 182 - - 29 29 - 316 - 192 105.5 - 5, 29 5, 29 MEAN - - - - 101.8 (a) TABLE 3.3.6 AMPLITUDE ON THE RECORDER, CR-1652 rabbit no. 1266, 4th strip (a) This value is set as a 100-0/o nicotine contraction (maximum nicotine amplitude). TABLE AMPLI7 rabbit (a) Tt s4%sCszooi
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® REPORT A o5oo/3o17.o9 RL17 (R) B3o ® STEP NUMBER N ORGAN BATH CONCENTRATION AMPLITUDE ACCORDI G TO TABLE A NORADRE- NALINE (umoi/1) REF. SUBST. (umol/1) TEST SUBST. (umol/1) ABS. mm) RELATIVE TO PRECEDING NORADRENALINE AMPLITUDE (0/0) MAXIMUM NICOTINE AMPLITUDE (0/0) 2 0.1 - - 139 - - 5 316 - 14o loo.7 - 8 0.1 - - 153 - - 11 -. - 56.2 113 73.9 66.9 14 0.1 - - 1o4 - - 17 - - 31.6 1o3 99.0 89.6 2o 0.1 -- - 151 - -. 23 - - 5.62 22 14.6 13.2 26 0.1 - - 118 - - 29 - 316 - 142 12o.3 - 5, 29 MEAN - - - - 110.5 (a) TABLE 3.3.7 AMPLITUDE ON THE RECORDER, CR-1652 rabbit no. 1267, 2nd strip (a) This value is set as a 100-0/o nicotine contraction (maximum nicotine amplitude). oszsCszooT
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0 REPORT A o5oo/3o17.o9 RL17 (R) Al ~ STEP NUMBER ORGAN BATH CONCENTRATION AMPLITUDE CCORDING TO A TABLE A NORADRE- REF. TEST ABS. RELATIVE TO NALINE SUBST. SUBST. PRECEDING MAXIMUM NORADRENALINE NICOTINE AMPLITUDE AMPLITUDE (umo:/1) (umol/1) (umol/1) (mm) (0/0) (0/0) 2 5 8 11 14 17 2o 23 26 29 5, 9 A N 0.1 - 316 0.1 - 0.1 - 0.1 - - 0.1 - 316 0.0 5.62 3.1%, 89 1o3 115.7 87 4o 46.o 97 29 29.9 105 1 o.95 105 155 147.6 1.7 ) 4.9 22.7 o.72 TABLE 3.3.8 AMPLITUDE O rabbit no. N TH 1269 E RECORDER, CR-1652 , 3rd strip (a) This value I is set as a 100-0/o nicotine cont raction (maximum nicotine amplitude). REPORT A 5, 29 TABLE 3. AMPLITUI rabbit i (a) Thi: TBMECzo0T
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0 REPORT A o500/3o17.o9 RL17 (R) A2 STEP NUMBER ORGAN BATH CO[•"-.TRATION AMPLITUDE ACCORDING TO TABLE A NORADRE- RE-'. TEST ABS. RELATIVE TO NALINE SUESSY. SUBST. PRECEDING MAXIMUM NORADRENALINE NICOTINE AMPLITUDE AMPLITUDE (umol/1) (umol/1) (umol/1) (mm) (0/0) (0/0) 2 5 8 11 14 17 2o 23 26 29 5, 9 AN 0.1 - 0.1 - 0.1 - 0.1 - 0.1 - - - 316 - -. - - - - - 316 - - - - 56.2 - 31.6 - 17.8 - - - 88 - 124 14o.9 88 - 123 139.8 99 - 122 123.2 97 - 100 io3.1 98 - 156 159.2 - 15o.1 ) - - - 93.1 - 82.1 - 68.7 - - TABLE 3.3.9 AMPLITUDE ON THE RECORDER, CR-1652 rabbit no. 1269, 4th strip (a) This value is set as a loo-o/o nicotine cont raction (maximum nicotine amplitude). 5, 29 N TABLE 3.; AMPLITUDf rabbit n( (a) This z8zsUs"GooT
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REPORT A o5oo/3o17.o9 RL17 (R) A3 STEP NUMBER ORGAN BATH CONCENTRATION AMPLITUDE ACCORDING TO TABLE A NORADRE-. REF. TEST ABS. RELATIVE TO NALINE SUBST. SUBST. PRECEDING MAXIMUM NORADRENALINE NICOTINE AMPLITUDE AMPLITUDE (umol/1) (umol/1) (umol/1) (mm) (0/0) (0/0) 2 S 8 11 14 17 2o 23 26 29 5, 9 AN 0.1 - 0.1 - 0.1 -. 0.1 - 0.1 - - - 316 - - - - - - - 316 - - - . 3.16 - 5.62 - 10.0 - - - 115 - 142 123.5 118 - 2 1.7 127 - 24 18.9 135 - 7o 51.9 137 - 191 139.4 - 131.5 ) - - - 1.3 - 14.4 - 39.5 - - TABLE 3.3.1o AMPLITUDE ON THE RECORDER, CR-1652 rabbit no. 127o, 1st strip (a) This value is set as a 100-0/o nicotine cont raction (maximum nicotine amplitude). ESZSes~ooi A
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0 REPORT A oSoo/3oi7.o9 RL17 (R) A4 ® STEP NUMBER ORGAN BATH CONCENTRATION AMPLITUDE ACCORDING TO TABLE A NORADRE- REF. TEST ABS. RELATIVE TO NALINE SUBST. SUBST. PRECEDING MAXIMUM NORADRENALINE NICOTINE AMPLITUDE AMPLITUDE (umol/1) (umol/1) (umol/1) (mm) (0/0) (0/0) 2 5 8 11 14 17 2o 23 26 29 5, 9 A 0.1 - 0.1 - 0.1 - 0.1 - 0.1 - N - - 316 - -. - - - - - 316 - - - -. 17.8 - 31.6 - 56.2 - - - 92 - 125 135.9 93 - 110 118.3 95 - 13o 136.8 93 - 137 147.3 94 - 156 166.0 - 151.o ) - - . 78.3 - 90.6 - 97.5 - - TABLE 3.3.1 1 AMPLITUDE O rabbit no. N THE RECORDER, 127o, 2nd strip CR-1652 (a) This value is set as a loo-o/o nicotine cont raction (maximum nicotine amplitude). 5, 29 i TABLE 3. AMPLITUD rabbit n (a) This VC7m(,FjC QQ i'
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REPORT A o5oo/3o17.o9 RL17 (R) A23 STEP NUMBER ORGAN BATH CONCENTRATION AMPLITUDE ACCORDING TO TABLE A NORADRE- REF. TEST ABS. NALINE SUBST._ SUBST. (umol/1) (umol/1) (umol/1) (mm) ~1 0 7 N C- G o- 0 RELATIVE TO 0 PRECEDING MAkIMUM cn NORADRENALINE NICOTINE cn 0 =r AMPLITUDE AMPLITUDE CD `rl (o/o) (0/0) 0 ~ ~ =r 2 0.1 - - 1o3 - - 5 - 316 - 128 124.3 - 8 0.1 - - 96 - - 11 - - 562.o 57 59.4 39.6 14 0.1 - - 99 - - 17 - - 316.o 74 74.7 49.8 2o 0.1 -. - 111 - - 23 - - 178.o 84 75.7 50.5 26 0.1 - - 111 - - 29 -. 316 - 195 175.7 - 5, 29 MEAN - - - - 15o.o (a) TABLE 3.4.1 AMPLITUDE ON THE RECORDER, CR-177oA rabbit no. 1248, ist strip (a) This value is set as a loo-o/o nicotine contraction (maximum nicotine amplitude). S8MES~00T a n STEP NU ACCORDI TABLE P 2 5 8 11 14 17 2o 23 26 29 5, 29 TABLE AMPLIT( rabbit (a) Th
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REPORT A o500/3o17.o9 RL17 (R) A24 STEP NUMBER ING O O ORGAN BATH CONCENTRATION AMPLITUDE T RD ACC TABLE A NORADRE- REF. TEST ABS. RELATIVE TO NALINE SUBST. SUBST. PRECEDING MAXIMUM NORADRENALINE NICOTINE AMPLITUDE AMPLITUDE (umol/1) (umol/1) (umol/1) (mm) (0/0) (0/0) 2 5 8 11 14 1 7 20 23 26 29 5, 9 AN 0.1 - 0.1 - 0.1 - 0.1 - 0.1 - - - 3i6 -. - - -. - - - 316 - - - - 100.0 - 56.2 - 31.6 - - - 91 - 1o7 117.6 96 - 17 17.7 108 - 17 15.7 111 - 7 6.3 12o - 178 148.3 - 133.o ) - - 13.3 - 11.8 - 4.7 - - TABLE 3.4.2 AMPLITUDE ON THE RECORDER, CR-177oA rabbit no. 1248, 2nd strip (a) This value is set as a 10o-o/o nicotine cont raction (maximum nicotine amplitude). 98Z6E5~ 00Z 5, 29 TABLE 3. AMPLITUI rabbit i (a) Thi
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REPORT STEP NUMBER ORGAN BA.ri CONCENTRATION AMPLITUDE ACCORD: 4G TO TABLE A. NORADRE- NALINE REF. SUBST. TEST SUBST. ABS. RELATIVE TO PRECEDING NORADRENALINE AMPLITUDE MAXIMUM NICOTINE AMPLITUDE 2 0.1 - - 1"' - - 5 - 316 - 6o 352.9 - B o.1 - - 17 - 11 - - 31.6 1 5.9 2.0 14 0.1 - - 27 - ^ 17 - - 56.2 2 7.4 2.5 20 0.1 - - 32 - - 23 - - 100.0 10 31.3 1o.6 26 0.1 - - 40 - - 29 - 316 - 94 235.o - TABLE 3.4.3 AMPLITUDE ON THE RECORDER, CR-177oA rabbit no. 1416, 3rd strip (a) This value is set as a loo-o/o nicoti:ine contraction (maximum nicotine amplitude). STEP N ACCORD TABLE 2 5 8 11 14 17 2o 23 5, 29 TABLE AMPLII rabbit (a) Tt 4SZSCGzo0T
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STEP NUMBER ORGAN BATH CONCENTRATION AMPLITUDE ACCORDING TO TABLE A NORADRE- NALINE (umol/1) REF. SUBST. (umol/1) TEST SUBST. (umoi/1) ABS. mm) RELATIVE TO PRECEDING NORADRENALINE AMPLITUDE (o/o) MAXIMUM NICOTINE AMPLITUDE (0/0) 2 0.1 109 5 - 316 112 1o2.8 - 8 0.1 128 11 - 31.6 7 5.5 5.4 14 0.1 137 17 - 56.2 29 21.2 21.o 2o 0.1 144 23 - 100.0 38 26.4 26.1 26 0.1 146 29 - 316 145 99.3 - 5, 29 MEAN 101.1 (a) - TABLE 3.4.4 AMPLITUDE ON THE RECOI:DER, rabbit no. 1262, 1st strip CR-177oA (a) This value is set as a loo-o/o nicotine contraction (maximum nicotine amplitude). sSZSEs~ooT
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REPORT A o500/3o17.09 RL17 (R) A27 STEP NUMBER ACCORDING TO ORGAN BATH CONCENTRATION AMPLITUDE TABLE A NORADRE- NALINE REF. SUBST. TEST SUBST. ABS. RELATIVE TO PRECEDING NORADRENALINE AMPLITUDE MAXIMUM NICOTINE AMPLITUDE (umol/1) (umol/1) (umol/1) (mm) (0/0) (o/o) 2 0.1 114 5 - 316 119 1o4.4 3 0.1 13o 11 - 178.0 46 35.4 34.3 14 0.1 144 17 - 316.o 51 35.4 34.3 2o 0.1 149 23 - 562.o 49 32.9 31.9 26 0.1 153 29 - 316 156 1o2.o - 5, 29 MEAN 1o3.2 (a) TABLE 3.4.5 AMPLITUDE ON THE RECORDER, CR-177oA rabbit no. 1262, 2nd strip (a) This value is set as a loo-o/o nicotine cont raction (maximum nicotine amplitude). ssZsEs~ooT 5, 29 TABLE AMPLIT rabbit (a) Th
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REPORT A o5oo/3oi7.o9 RL17 (R) A28 n f STEP NUMBER ORGAN BATH CONCENTRATION AMPLITUDE ACCORDING TO TABLE A NORADRE- REF. TEST ABS. RELATIVE TO NALINE SUBST. SUBST. PRECEDING MAXIMUM NORADRENALINE NICOTINE AMPLITUDE AMPLITUDE (umol/1) (umol/1) (umol/1) (mm) (0/0) (0/0) 2 0.1 - - 15o - - 5 - 316 - 171 114.o - 8 0.1 - - 17o - - 11 - - 100.0 37 21.8 19.5 14 0.1 - - 187 - . 17 - - 56.2 17 9.1 8.1 2o 0.1 -. - 167 - - 23 - - 31.6 0 0 0 26 0.1 - - 172 - - 29 - 316 - 188 1o9.3 - 5, 29 MEAN - - - - 111.7 (a) TABLE 3.4.6 AMPLITUDE ON THE RECORDER, CR-177oA rabbit no. 1263, 2nd strip (a) This value is set as a loo-o/o nicotine contraction (maximum nicotine amplitude). OVMGGVO0T
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REPORT A o5oo/3o17.o9 RL17 (R) A29 STEP NUMBER ORGAN BATH CONCENTRATION AMPLITUDE ACCORDING TO TABLE A NORADRE- REF. TEST ABS. RELATIVE TO NALINE SUBST. SUBST. PRECEDING MAXIMUM NORADRENALINE_ NICOTINE AMPLITUDE AMPLITUDE (umol/1) (umol/1) (umol/1) (mm) (0/0) (0/0) 2 5 8 11 14 17 20 23 26 29 5, 9 AN 0.1 - 0.1 - 0.1 - 0.1 - 0.1 -. - - 316 - - - - - - -. 316 - -. - - 31.6 -- - 56.2 - 100.0 - - - 91 - 91 100.0 103 - 1 o.97 108 - 2 1.9 108 - 9 8.3 98 - 126 128.6' - 114.3 ) - - - 0.85 - 1.7 - 7.3 - - TABLE 3.4.7 AMPLITUDE ON THE RECORDER, CR-177oA rabbit no. 1433, 3rd strip (a) This value is set as a 100-0/o nicotine cont raction (maximum nicotine amplitude). IGzsUs~ooi ®
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I 0 REPORT A o5oo/3o17.o9 RL17 (R) A3o STEP NUMBER CCORDING TO ORGAN BATH CONCENTRATION AMPLITUDE A TABLE A NORADRE-. REF. NALINE SUBST. TEST SUBST. ABS. RELATIVE TO PRECEDING NORADRENALINE AMPLITUDE MAXIMUM NICOTINE AMPLITUDE (umol/1) (umol/1) (umol/1) (mm) (0/0) (0/0) 2 0.1 1o4 5 - 316 110 105.8 - 8 0.1 114 11 - 178.o 23 2o.2 17.3 14 0.1 114 17 - 316.o 25 21.9 18.7 2o 0.1 98 23 - 562.0 3o 3o.6 26.1 26 0.1 99 29 - 316 127 128.3 - 5, 29 MEAN 117,1 (a) - TABLE 3.4.8 AMPLITUDE ON THE RECORDER, CR-177oA rabbit no. 1433, 4th strip (a) This value is set as a 100-0/o nicotine aont ract=on (maximum nicotine amplitude). .u, 4q*_v.l'zti,fi`r w >SJ, N il l zszs~s~aoz ® REPORT 5, 29 TABLE : AMPLITI rabbit (a) Th N ®
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® REPORT A o5oo/3o17.o9 RL21 (R) B7 STEP NUMBER ORGAN BATH ACCORDING TO TABLE A NORADRE- NALINE (umol/1) z W ' REPORT i 0 ~ w c ~ -- CONCENT RATION AMPLITUDE c: , '~ STEP NUP _ ~ 0 ACCORDIt REF. TEST ABS. RELATIVE TO 0 TABLE A SUBST. SUBST. PRECEDING MAXIMUM cn 1 umol/1) (umol/i) mm) NORADRENALINE AMPLITUDE (0/0) NICOTINE AMPLITUDE (0/0) ' U) c :7 ~ cD ~ o' 2 0.1 - 5 - 316 8 0.1 - 11 - - 14 0.1 - 17 - - 2o 0.1 - 23 - - 26 0.1 - 29 - 316 5, 29 MEAN - - TABLE 3.4.9 AMPLITUDE ON THE RECORDER, CR-177oA rabbit no. 1274, 3rd strip ® ~ 0 - -- - 118 - - i c ~ 2 - 141 119.5 - ~n 5 - 127 - - g 178.0 75 59.1 44.8 a 11 - 132 - - ~ 14 316.o 93 7o.5 53.5 17 - 132 - - 2o 562.o 98 74.2 56.3 ' 23 - 143 - - 26 - 206 144.1 - 29 - - 131.8 (a) , 29 (a) This value is set as a 1oa-o/o nicotine contraction (maximum nicotine amplitude). CszsCs~ooz TABLE 3. AMPLITUE rabbit r (a) Thi:
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REPORT A o500/3o17.o9 RL17 (R) A6 STEP NUMBER ACCORDING TO ORGAN BATH CONCENTRATION AMPLITUDE TABLE A NORADRE- NALINE (umol/1) REF. SUBST. (umol/1) TEST SUBST. (umol/1) ABS. mm) RELATIVE TO PRECEDING NORADRENALINE_ AMPLITUDE (0/0) MAXIMUM NICOTINE AMPLITUDE (0/0) 2 0.1 69 5 - 316 89 124.6 - 8 0.1 72 11 - 562.o 92 127.8 90.1 14 0.1 77 17 -. 316.o 1o6 137.7 97.1 2o 0.1 77 23 - 178.0 117 151.9 io7.1 26 0.1 78 29 - 316 124 159.o 5, 29 MEAN - - - - 141.8 (a) TABLE 3.5.1 AMPLITUDE ON THE RECORDER, CR-1772 rabbit no. 1248, 3rd strip (a) This value is set as a 100-0/o nicotine contraction (maximum nicotine amplitude). VG%6EG'24A00T 5, 29 TABLE 3. AMPLITU: rabbit n (a) This
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REPORT A o5oo/3o17.09 RL17 (R) A7 STEP NUMBER ORGAN BATH CONCENTRATION AMPLITUDE ACCORDING TO TABLE A NORADRE-. REF. TEST ABS. RELATIVE TO NALINE SUBST. SUBST. PRECEDING MAXIMUM - NORADRENALINE NICOTINE AMPLITUDE AMPLITUDE (umol/1) (umol/1) (umol/1) (mm) (0/0) (0/0) 2 5 8 11 14 17 2o 23 26 29 5, 9 A 0.1 - 0.1 0.1 0.1 0.1 - N - - 316 - - 316 - 00.0 56.2 31.6 - 47 72 153.2 52 8o 153.8 52 90 173.1 52 90 173.1 59 105 178.o - 165.6 ) 2.9 1o4.5 lo4.5 TABLE 3.5.2 AMPLITUDE O rabbit no. N THE RECORDER, 1248, 4th strip CR-1772 (a) This value is set as a loo-o/o nicotine cont raction (maximum nicotine amplitude). S676ES-f0A00Z L
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0 0 STEP NUMBER ORGAN BfLTH CONCENTRATION AMPLITUDE ACCORDING TO TABLE A NORADRE- REF. TEST ABS. RELATIVE TO NALIN_E_ SUBST. SUBST. PRECEDING MAXIMUM NORADRENALINE NICOTINE AMPLITUDE AMPLITUDE (umol/1) (umoi/i) (umol/1) (mm) (0/0) (0/0) 2 5 8 11 14 17 2o 23 26 29 5, 9 A 0.1 - 0.1 - 0.1 - 0.1 - 0.1 - N - - 316 -. - - - - - - 316 - -. - - 31.6 - 56.2 - 100.0 - - - 17 - 48 282.4 25 - 39 156.o 32 - 61 19o.6 34 68 2oo.o 32 -. 73 228.1 - 255.3 ) - - 61.1 - 74.7 - 78.3 - TABLE 3.5.3 AMPLITUDE O rabbit no. N THE RECORDER, 1416, 1st strip CR-1772 (a) This value is set as a ioo-o/o nicotine cont raction (maximum nicotine amplitude). Ti,BLE AMPLIT rabbit (a) Th 777 0irr7plu}•. . } 96%6E6Z00T
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19 ® 0 STEP NUMBER ORGAN BATH CONCENTRATION AMPLITUDE CCORDING TO A TABLE A NORADRE- REF. TEST ABS. RELATIVE TO NALINE SUBST. SUBST. PRECEDING MAXIMUM NORADRENALINE NICOTINE AMPLITUDE AMPLITUDE (umol/1) (umol/1) (umol/i) (mm) (0/0) (0/0) 2 5 8 11 14 17 2o 23 26 29 5, 9 AN 0.1 - 0.1 - 0.1 - 0.1 -. 0.1 - - - 316 - - - - - - -. 316 - - - - 178.o - 316.o - 562.o -- - - 21 31 35 34 43 43 48 54 48 64 - -. 147.6 - 97.1 - 100.0 - 112.5 - 133.3 14o.5 ) _ - - 69.1 - 71.2 -. 80.1 - - TABLE 3.5.4 AMPLITUDE ON THE RECORDER, CR-1772 rabbit no. 1416, 2nd strip (a) This value is set as a 1oo-o/o nicotine contraction (maximum nicotine amplitude). 4szsES~ooT REPORT A 5, 29 ! TABLE 3.: AMPLITUDE rabbit nc (a) This
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REPORT A o500/3017.09 RL17 (R) Ato STEP NUMBER ORGAN BATH CONCENTRATION AMPLITUDE ACCORDING TO ?'ABL_E A NORADRE- REF. TEST ABS. RELATIVE TO NALINE SUBST. SUBST. PRECEDING MAXIMUM NORADRENALINE NICOTINE AMPLITUDE AMPLITUDE (umol/1) (umol/1) (umol/1) (mm) (0/0) (0/0) 2 5 8 11 14 17 2o 23 26 29 5, 29 AN 0.1 - 0.1 - 0.1 - 0.1 - 0.1 - - - 316 -. - - - - - - 316 - - - - 31.6 - 56.2 - 100.0 - - - 54 71 77 39 85 5o 90 88 93 97 - - 131.5 - 50.6 - 58.8 -. 97.8 - 1o4.3 117.9 ) - - - 42.9 - 49.9 - 83.o - - TABLE 3.5.5 ® AMPLITUDE ON THE RECORDER, CR-1772 rabbit no. 1262, 3rd strip (a) This value is set as a loo-o/o nicotine contraction (maximum nicotine amplitude). .•~~ ..... . , . '~~.Y'~ ... 1.~ . AY~'~:~'.!.'.~'tT.:Y;1+~ STEP NUMI ACCORDIN( TABLE A 2 5 8 11 14 17 2o 23 26 29 5, 29 ~ TABLE 3.: AMPLITUDt rabbit nc (a) This 86~6E60% 0 QZ
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STEP NUMBER ORGAN BATH CONCENTRATION AMPLITUDE ACCORDING TABLE A TO NORADRE- NALINE REF. SUBST. TEST SUBST. ABS. RELATIVE TO PRECEDING NORADRENALINE AMPLITUDE_ MAXIMUM NICOTINE AMPLITUDE (umol/i) (umol/1) (umol/1) (mm) (0/0) (0/0) 2 0.1 34 5 - 316 3o 88.2 8 0.1 49 11 - 178.o 31 63.3 8o.5 14 0.1 54 17 - 316.o 32 59.3 75.4 2o 0.1 6o 23 - 562.o 3o 50.0 63.6 26 0.1 61 29 - 316 42 68.9 - 5, 29 ME AN - 78.6 (a) TABLE 3.5. 6 AMPLITUDE rabbit no. ON THE RECORDER, 1262, 4th strip CR-1772 (a) This value is set as a 100-0/o nicotine contr action (maximum nicotine a.•.plitude). ss%sCszooz REPORT . STEP NUI ACCORDI, TABLE A 2 5 8 11 14 17 2o 23 26 29 5, 29 TABLE 3. AMPLITUI rabbit j (a) Thie
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REPORT A o5oo/3o17.o9 RL17 (R) A12 STEP NUMBER ORGAN BATH ACCORDING TO TABLE A NORADRE- NALINE (umol/1) REPORT 1 STEP NU CONCENTRATION AMPLITUDE o' ACCORDI REF. TEST ABS. RELATIVE TO 0 0 TABLE A SUBST. SUBST. PRECEDING MAXIMUM ~ NORADRENALINE NICOTINE N 0 AMPLITUDE AMPLITUDE a CD ~ (umol/1) (umol/1) (mm) (0/0) (0/0) 0 ~ 2 0.1 - 5 - 316 8 0.1 - 11 - - 14 0.1 - 17 - - 2o 0.1 - 23 - - 26 0.1 29 - 316 5, 29 MEAN - - TABLE 3.5.7 AMPLITUDE ON THE RECORDER, CR-1772 rabbit no. 1263, 3rd strip (a) This value is set as a 100-0/o ooUsUGzooi - 114 - - - 12o to5.3 - - 138 - - 562 .0 124 89.9 89.1 _ - 152 - - 316.0 109 71.7 71.1 - 162 - - 178.o 125 77.2 76.5 - 139 - - - 134 96.4 - - - 100.9 (a) - nicotine contraction (maximum nicotine amplitude). 0 :3 2 5 8 11 14 17 2o 23 26 29 5, 29 TABLE 3 AMPLITU: rabbit i (a) Thi:
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0 REPORT A o5oo/3o17.o9 RL17 (R) A13 STEP NUMBER ACCORDING TO TABLE A 0 ORGAN BATH CONCENTRATION AMPLITUDE NORADRE- REF. TEST ABS. RELATIVE TO NALINE SUBST. SUBST. PRECEDING MAXIMUM NORADRENALINE NICOTINE AMPLITUDE AMPLITUDE (umol/1) (umol/1) (umol/1) (mm) (0/0) (o/o) 2 5 8 11 14 17 2o 23 26 29 5, 9 A 0.1 - 0.1 - 0.1 - 0.1 - 0.1 - N - - 16 - - - - - - 316 - - - -. 100.0 - 56.2 - 31.6 - - 136 159 116.9 168 - 137 81.5 185 - 155 83.8 186 - 86 46.2 169 - 186 110.1 - 113.5 ) - - 71.8 - 73.8 - 4o.7 - - - TABLE 3.5.8 AMPLITUDE O rabbit no. N THE RECORDER, 1263, 4th strip CR-1772 (a) This vdlue is set as a loo-o/o nicotine cont raction (maximum nicotine amplitude). TOE6E6GOOT
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1® ® etEPORT A o5oo/3o17.o9 RL17 (it) A14 STEP NUMBER ORGAN BATH CONCENTRATION AMPLITUDE CCORDING TO A TABLE A NORADRE- REF. TEST ABS. RELATIVE TO NALINE SUBST. SUBST. PRECEDING MAXIMUM NORADRENALINE NICOTINE AMPLITUDE AMPLITUDE (umol/1) (umol/1) (umol/1) (mm) (0/0) (o/o) 2 5 8 11 1 4 17 2o 23 26 29 5, 29 MEAN TABLE 3.5.9 AMPLITUDE ON THE RECORDER, rabbitt no. 1433, 2nd strip (a) This value is set as a ZO(.V(.6"MOT - - 111 - - 316 - 79 71.2 - - - 125 - - - 10.0 .o 0 0 -. - 129 - - - 17.8 12 9.3 9.2 - -. 119 - .. - 31.6 4o 33.6 33.2 - - 1o2 - -. 316 - 134 131.4 - - - - lol.3 (a) CR-1772 loo-o/o nicotine contraction (maximum nicotine amplitude). 5 8 11 14 17 2o 23 26 29 5, 29 I TABLE 3. AMPLITUD rabbit n (a) This
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STEP NUMBER ORGAN BATH CONCENTRATION AMPLITUDE ACCORDING TO TABLE A NORADRE-. REF. TEST ABS. RELATIVE TO NALINE SUBST. SUBST. PRECEDING MAXIMUM NORADRENAL_INE_ NICOTINE AMPLITUDE AMPLITUDE (umol/1) (umol/1) (umol/1) (mm) (0/0) (0/0) 2 5 8 11 14 17 2o 23 26 29 5, 9 AN 0._1 -. 0.1 - 0.1 - 0.1 - 0.1 - - - 316 - -. - - - - - 316 - - -. 31.6 - 17.8 - 10.0 - - - 114 119 133 82 139 39 144 5 146 17o - - 1o_4.4 - 61.7 - 28.1 - 3.5 - 116.4 11o.4 (a) - - 55.9 - 25.5 - 3.2 - - TABLE 3.5.1o AMPLITUDE ON THE RECORDER, CR-1772 rabbit n-. 1274, 4th strip (a) This value is set as a loo-o/o nicotine contraction (maximum nicotine amplitude). COMt..v(~.00 i~ TABLE AMPLIT rabbit (a) Th
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REPORT A o5oo/3ol7.o9 RL17 (R) A16 STEP NUMBER ORGAN BATH CONCENTRATION AMPLITUDE ACCORDING TO TABLE A NORADRE-. NALINE REF. SUBST. TEST SUBST. ABS. RELATIVE TO PRECEDING NORADRENALINE AMPLITUDE MAXIMUM NICOTINE AMPLITUDE (umol/1) (umol/1) (umol/1) (mm) (0/0) (0/0) 2 0.1 -. - 1o4 - - 5 - 316 - 133 127.9 - 8 0.1 - - 118 - - 11 -. - 10.0 2 1.7 1.4 14 0.1 - - 124 - - 17 - - 17.8 35 28.2 22.4 2o 0.1 - - 134 - - 23 - -. 31.6 1o2 76.1 6o.5 26 0.1 - - 128 - - 29 - 316 - 158 123.4 - 5, 29 MEAN - - - - 125.7 (a) - TABLE 3.5.11 AMPLITUDE ON THE RECORDER, CR-1772 rabbit no. 1265, 4th strip (a) This value is set as a loo-o/o nicotine contraction (maximum nicotine amplitude). REPORT 5, 29 TABLE . AMPLITI rabbit (a) Th t70Mm~OOZ
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I 4 nEPORT A o5oo/3o17.o9 RL17 (R) A17 0 STEP NUMBER ORGAN BATH CONCENTRATION AMPLITUDE ACCORDING TO TABLE A NORADRE- REF. TEST ABS. RELATIVE TO NAL_INE_ SUBST. SUBST. PRECEDING NORADRENALINE AMPLITUDE MAXIMUM NICOTINE AMPLITUDE (umol/1) (umol/1) (umol/1) (mm) (0/0) (o/o) 2 0.1 - - 172 - - 5 -. 316 - 182 1o5.8 - 8 0.1 - - 181 - - 11 -. - 31.6 88 48.6 44.7 14 0.1 - - 199 - - 17 - - 17.8 33 16.6 15.3 2o 0.1 - - 179 - - 23 - - 10.0 0 0 0 26 0.1 - - 182 - - 29 - 316 - 2o3 111.5 - 5, 29 MEAN - - - - 1o8.7 (a) TABLE 3.5.12 AMPLITUDE ON THE RECORDER, CR-1772 rabbit no. 1266, 1st strip (a) This value is set as a loo-o/o nicotine contraction (maximum nicotine amplitude). so~sXG~:oOT 5, 29 TABLE 3 AMPLITUI rabbit (a) Thi
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0 I 0 REPORT A o5oo/3o17.o9 RL17 (R) A18 STEP NUMBER ORGAy_ BATH CONCENTRATION AMPLITUDE ACCORDING TO TABLE A NOFADRE-. REF. TEST ABS. RELATIVE TO NALINE SUBS.'. SUBST. PRECEDING NORADRENALINE AMPLITUDE (umol/1) (umol/1) (umol/1) (mm) (0/0) 5 - 316 2 0.1 8 0.1 1 1 -. 14 0.1 17 - 2o 0.1 23 - 26 0.1 29 - 5, 29 MEAN 316 TABLE 3.5.13 AMPLITUDE ON THE RECORDER, CR-1772 rabbit no. - , 1st strip 112.3 (a) Q O 0 REPORT . STEP NU ACCORDI TABLE A MAXIMUM NICOTINE AMPLITUDE (o/o) cD U) 0 :r CD ~ 0 ~ 0 zr c 2 ~ - caa 5 8 20 4 A 11 . a D 14 61.1 17 2o 90.1 23 26 29 5, 29 (a) This value is set as a loo-o/o nicotine contraction (maximum nicotine amplitude). 115 134 140 32 159 109 168 17o 175 116.5 22.9 68.6 lol.2 189 108.0 TABLE : AMPLIT( rabbit (a) Th 90E6C6%00Z
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® REPORT A o500/3017.09 RL17 (R) A19 STEP NUMBER ORGAN BATH CONCENTRATION AMPLITUDE ACCORDING TO TABLE A NORADRE- REF. TEST ABS. NALINE SUBST. SUBST. (umol/1) (umol/1) (umol/1) (mm) ® RELATIVE TO PRECEDING MAXIMUM NORADRENALINE NICOTINE AMPLITUDE AMPLITUDE (0/0) (o/o) 2 5 8 11 14 17 2o 23 26 29 5, 9 AN 0.1 - 0.1 - 0.1 - 0.1 - 0.1 - 316 6 1.6 17.8 10.0 112 121 108.0 13o 61 46.9 147 29 19.7 158 27 169 168 99.4 1o3.7 ) - 45.2 19.0 1.2 TABLE 3.5.14 AMPLITUDE ON rabbit no. - THE RECORDER, , 2nd strip CR-1772 (a) This value is set as a 100-0/o nicotine cont raction (maximum nicotine amplitude). 4oUsUGzooi REPORT STEP NL ACCORDI TAB LE I 2 5 B 11 14 17 2o 23 26 29 5, 29 TABLE AMPLIT rabbit (a) Th
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® ® a REPORT A o500/3o17.o9 RL17 (R) A2o STEP NUMBER ORGAN BATH CONCENTRATION AMPLITUDE CCORDING TO A TABLE A NORADRE_- REF. TEST ABS. RELATIVE TO NALINE SUBST. SUBST. PRECEDING MAXIMUM NORADRENALINE NICOTINE AMPLITUDE AMPLITUDE (umol/1) (umol/1) (umol/1) (mm) (0/0) (0/0) 2 5 8 11 14 17 2o 23 26 29 5, 29 MEAN TABLE 3.5.15 AMPLITUDE ON THE RECORDER, rabbit no. - , 3rd strip (a) This value is set as a soMUCzooT 110 316 132 12o.o - 132 10.0 18 13.6 11.9 149 17.8 80 53.7 46.9 162 31.6 128 79.0 68.9 174 316 190 1o9.2 - 114.6 (a) CR-1772 100-0/o nicotine contraction (maximum nicotine amplitude). . 1: 5, 29 TABLE : AMPLITI rabbit (a) Th >~^4' ~; r"IOh~•,
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REPORT A o500/3017.09 RL17 (R) A21 STEP NUMBER ORGAN BATH CONCENTRATLON AMPLITUDE ACCORDING_ TO TABLE A NORADRE- NALINE (umol/1) REF. SUBST. (umol/1) TEST SUBST. (umol/1) ABS. RELATIVE TO PRECEDING NORADRENALINE AMPLITUDE (mm) (o/o) MAXIMUM NICOTINE AMPLITUDE (0/0) 2 0.1 - - 110 - - 5 - 316 - 114 1o3.6 - 8 0.1 - - 136 - - 11 - - 31.6 7o 51.5 53.5 14 0.1 - - 154 - - 17 - - 17.8 41 26.6 27.6 ?o 0.1 - - 164 - -. 23 - - 10.0 7 4.3 4.5 26 0.1 - - _ 171 - - 29 - 316 - 152 88.9 - 5, 29 MEAN - - - - 96.3 (a) TABLE 3.5.16 AMPLITUDE ON THE RECORDER, CR-1772 rabbit no. - , 4th strip (a) This value is set as a 100-0/o nicotine contraction (maximum nicotine amplitude). soCsUszoo1 RE PO RT STEP NU ACCORDI TABLE A 2 5 8 11 14 17 2o 23 26 29 5, 29 TABLE : AMPLITI rabbit (a) Th
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REPORT A o500/3017.09 RL21 (R) A4 (GD) Z m 0 5 N C STEP NUMBER ORGAN BAT H CONCENTRATION AMPLITUDE C= ~ ACCORDING TO 0 TABLE A NORADRE- NALINE_ umol/1) REF. SUBST. umol/1) TEST SUBST. umol/1) ABS. RELATIVE TO PRECEDING NORADRENALINE AMPLITUDE (mm) (0/0) MAXIMUM NICOTINE AMPLITUDE (o/o) ~ N 0 ~ CD ~l 0 ~ ~ 2 5 8 11 14 17 2o 23 26 29 5, 29 AN 0._1 - 0.1 - 0.1 - 0.1 - 0.1 - - - 316 - - - - - - - 316 - - - - 562 - 316 - 178 -. - - 95 - 106 111.6 115 - 0 0 126 - 0 0 138 - 0 0 152 - 129 84.9 - 98.3 (a) - - - 0 - 0 - 0 -. - ~ c 3 (0 X C. =3 TABLE 3.6.1 AMPLITUDE ON THE RECORDE R, CR-1316A rabbit no. 1475, 1st str ip (a) This.value is set as a 100-0/o nicotine cont raction (maximum nicotine amplitude). OTE6US~OOZ RE PO RT STEP Nl ACCORD: TABLE l 2 5 8 11 14 17 2o 23 26 29 5, 29 TABLE AMPLIT rabbit (a) Th `f~
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0 0 REPORT A o5oo/3o17.o9 RL21 (R) A5 (GD) STEP NUMBER ORGAN BATH CONCENTRATION AMPLITUDE ACCORDING TO TABLE A NORADRE- REF. TEST ABS. RELATIVE TO NALINE SUBST. SUBST. PRECEDING MAXIMUM NORADRENALINE NICOTINE AMPLITUDE AMPLITUDE (umol/1) (umol/1) (umol/1) (mm) (0/0) (0/0) 2 5 8 lj 14 17 2o 23 26 29 5, 9 A 0.1 - - 87 - - - 316 - 91 1o4.6 - 0.1 - - 99 - - - - 100 0 0 0 0.1 - - 1o5 - - - - 56.2 0 0 0 0.1 - - 111 - - - - 31.6 0 0 0 0.1 - - 115 - - - 316 - 71 61.7 - N - - - - 83.2 (a) TABLE 3.6.2 AMPLITUDE O N THE RECORDER, CR-1316A rabbit no. 1475, 3rd strip (qi This value is set as a loo-o/o nicotine contraction .(maximum nicotine amplitude). 2 5 8 11 14 17 2o 23 26 29 5, 29 ME TABLE 3.5. A.IPLITUDE rabbit no. (a) This i TTUsE6ZooT
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REPORT A o5oo/3o17.o9 RL21 (R) A6 (GD) STEP NUMBER CCGR DING TO ORGAN BATH CONCENTRATION AMPLITUDE A I TABLE A NORADRE- REF. TEST ABS. RELATIVE TO NALINE SUBST. SUBST. PRECEDING MAXIMUM NORADRENALINE NICOTINE AMPLITUDE AMPLITUDE (umol/1) (umol/1) (umol/1) (mm) (0/0) (o/o) 2 5 8 11 14 17 2o 23 26 29 5, 9 AN 0.1 - 0.1 - 0.1 - 0.1 - 0.1 - 316 6 6.2 178 562 68 49 82 0 88 0 93 0 6 69 72.1 - 0 0 0 0 0 0 71.9 - 72.o (a) TABLE 3.6.3 AMPLITUCE ON THE RECORDER, CR-1316A rabbit no. 1316, 3rd strip (a) This value is set as a 100-0/o nicotine contraction (maximum nicotine amplitude). 4 YEGE`)ZO0T 5, 29 TABLE AMPLITi rabbit (a) Th
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ii 0 REPORT A o500/3017.09 RL21 (R) A7 (GD) D CA 2 0.1 90 ~ c 5 - 316 - 79 87.8 ~ cn 8 0.1 - - 116 - 11 - - 562 0 0 0 ~ 14 0.1 - - 122 - D< 17 - - 178 _ 0 0 0 ~ 2o 0.1 - - 126 - 2 3 -. - 56.2 0 0 0 26 0.1 - - 134 - 29 - 316 - 100 74.6 5, 29 MEAN 81.2 (a) STEP NUMBER ORGAN BATH CONCENTRATION AMPLITUD E c: ACCORDING TO _ _ a' ' TABLE A NORADRE- REF. TEST ABS. RELATIVE TO o © NALINE SUBST. SUBST. PRECEDING MAXIMUM (n NORADRENALINE NICOTINE F4, AMPLITUDE AMPLITUDE n ~ (umol/1) (umol/1) (umol/1) (mm) (0/0) (o/o) CD ~ 0 ~ 0 TABLE 3.6.4 AMPLITUDE ON THE RECORDER, CR-1316A rabbit no. 1314, 4th strip (a) This value is set as a loo-o/o nicotine contraction (maximum nicotine amplitude). . STEP NU ACCORDI TABLE A 2 5 8 11 14 17 2o 23 26 29 5, 29 TABLE : AMPLITI rabbit (a) Thi UMMIZ1ooT
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b STEP NUMBER ACCORDING TO TABLE A REPORT , 0 ORGAN BATH CONCENTRATION AMPLITUDE NORADkE- REF. TEST ABS. RELATIVE TO NALINE SUBST. SUBST. PRECEDING MAXIMUM NORADRENALINE NICOTINE AMPLITUDE AMPLITUDE (umol/1) (umol/1) (umol/1) (mm) (0/0) (0/0) 2 5 8 11 14 17 2o 23 26 29 5, 9 A 0.1 - 0.1 - 0.1 - 0.1 - 0.1 - N - - 316 - - - - - - - 316 - - - - 562.o - 316.o - 178.o - - - 105 - - 122 116.2 - 1o7 - - 0 0 0 118 - - 0 0 0 110 - - 0 0 0 96 - - 165 171.9 - - 144.1 (a) TABLE 3.7.1 AMPLITUDE O rabbit no.. N THE RECORDER, 1433, 1st strip CR-1773 (a) This value is set as a 100-0/o nicotine contraction (maximum nicotine amplitude). VZC6CS'%00T STEP NUt ACCORD It TABLE A 2 5 8 11 14 17 2o 23 26 29 5, 29 TABLE 3 AMPLITUI rabbit i (a) Thi:
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I 0 REPORT A o5oo/3o17.o9 RL17 (R) B21 0 STEP NUMBER ORGAN BATH CONCENTRATION AMPLITUDE CCORDING TO A TAPLE A NORADRE- REF. TEST ABS. RELATIVE TO NALINE SUBST. SUBST. PRECEDING MAXIMUM NORADRENALINE NICOTINE AMPLITUDE AMPLI::UDE (umol/1) (umol/1) (umol/1) (mm) (0/0) (o/o) 2 0.1 - - 125 - - 5 - 316 - 136 1o8.8 - 8 0.1 - - 136 - - ;t - - 178.o 0 0 0 14 0.1 - - 140 - - 17 - -- 316.0 0 0 0 2o 0.1 - - 148 - - 23 - - 562.o 0 0 0 26 0.1 - - 141 -. - 29 - 316 - 159 112.8 - 5, 29 MEAN - - - - 110.8 (a) TABLE 3.7.2 AMPLITUDE ON THE RECORDER, CR-1773 rabbit no. 1265, 3rd strip (a) This value is set as a loo-o/o nicotine contraction (maximum nicotine amplitudc). sTeGeszOoT I
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REPORT A o500/3o17.o9 RL17 (R) B22 z m O ~ q C. I Cr STEP NUMBER ORGAN BATH CONCENTRATION AMPLITUDE ~ a ACCORDING TO 0 TABLE A NORADRE- REF. TEST ABS. RELATIVE TO 0 NALINE umol/1) SUBST. umol/1) SUBST. PRECEDING MAXIMUM NORADRENALINE NICOTINE AMPLITUDE AMPLITUDE (umol/1) (mm) (o/o) (o/o) e!n n s CD n 0 R 0 2 0.1 - - 168 - s C ~ 5 - 316 - 190 113.1 - ~ 8 0.1 - - 188 -- 11 14 - 0.1 - - 178.0 - 0 0 0 2o6 - - A a :3 17 - - 316.o 0 0 0 2o 0.1 - - 185 - - 23 - - 562.o 0 0 0 26 0.1 - - 186 - - 29 -. 316 - 213 114.5 - 5, 29 ME AN - - - - 113.8 (a) - TABLE 3.7. 3 AMPLITUDE ON THE RECORDER, CR-1773 rabbit no. 1266, 2nd strip (a) This value is set as a loo-o/o nicotine contractinn (maximum nicotine amplitude). 9ZE6M2001
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STEP NUMBER ORGAN BATH CONCENTRATION AMPLITUDE ACCORDING TO TABLE A NORADRE- REF. TEST ABS. RELATIVE TO NALINE SUBST. SUBST. PRECEDING MAXIMUM NORADRENALINE_ NICOTINE AMPLITUDE AMPLITUDE (umol/1) (umol/1) (umol/1) (mm) (0/0) (0/0) 2 0.1 - - 12o - - 5 - 316 - 134 111.7 - 8 0.1 - - 139 - - 11 - - 178.o 73 52.5 49.2 14 0.1 - - 163 - - 17 - - 316.o 128 78.5 73.6 2o 0.1 - - 181 - -. 23 - - 562.o 154 85.1 79.8 26 0.1 - - 188 - - 29 - 316 - 191 lol.6 - 5, 29 MEAN - -• - - 1o6.7 (a) TABLE 3.8.1 AMPLITUDE ON THE RECORDER, CR-1274 rabbit no. 1249, 2nd strip (a) This value is set as a loo-o/o nicotine contraction (maximum nicotine amplitude). 4tiESUszooi A
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REPORT A o5oo/3o17.o9 RL17 (R) B12 STEP NUMBER ACCORDING TO ORGAN BATH CONCENTRATION AMPLITUDE TABLE A NORADRE- NALINE (umol/1) REF. SUBST. (umol/1) TEST SUBST. (umol/1) ABS. mm) RELATIVE TO PRECEDING NORADRENALINE AMPL.ITUDE (0/0) MAXIMUM NICOTINE AMPLITUDE (0/0) 2 0.1 - - 88 - 5 - 316 - 111 126.1 8 0.1 - - 110 - 11 - -. 31.6 11 10.0 9.1 14 0.1 - - 13o . - 17 - - 56.2 49 37.7 34.3 2o 0.1 - - 142 -. 23 -. - 100.0 75 52.8 48.o 26 0.1 - -. 147 - 29 - 316 - 138 93.9 5, 29 MEAN - - - - 110.0 (a) TABLE 3.8.2 AMPLITUDE ON THE RECORDER, CR-1274 rabbit no. 1429, 4th strip (a) This value is set as a 1oo-o/o nicotine contraction (maxirtlum nicotine amplitude). sTeGEGW0z
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REPORT A o5oo/3o17.o9 RL17 (R) B13 STEP NUMBER ORGAN BATH CONCENTRATION AMPLITUDE ACCORDING TO TABLE A NORADRE- REF. TEST ABS. RELATIVE TO NALTNE SUBST. SUBST. PRECEDING MAXIMUM NORADRENALINE_ NICOTINE AMPLITUDE AMPLITUDE (umol/1) (umol/1) (umol/1) (mm) (0/0) (0/0) 2 0.1 - - 63 - - 5 - 316 - 75 119.0 - 8 0.1 - - 82 - - 11 - -. 562.0 66 80.5 67.4 14 0.1 - - 1o3 - - 17 -. - 316.o 84 81.6 68.3 2o 0.1 - - 116 - - 23 - - 178.0 62 53.4 44.7 26 0.1 . - 132 - .- 29 - 316 - 158 119.7 - 5, 29 MEAN - - - - 119.4 (a) TABLE 3.8.3 AMPLITUDE ON THE RECORDER, CR-1274 rabbit no. 1251, 2nd strip (a) This. value is set as a loo-o/o nicotine contraction (maximum nicotine amplitude). _- T I 6TE6UG%OqZ
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F REPORT A o5oo/3o17.o9 RL17 (R) B14 STEP NUMBER CCORDING TO ORGAN BATH CONCENTRATION AMPLITUDE A TABLE A NORADRE- NALINE REF. SUBST. TEST SUBST. ABS. RELATIVE TO PRECEDING NORADRENA!.I_NE AMPLITUDE MAXIMUM NICOTINE AMPLITUDE (umol/1) (umol/1) (umol/1) (mm) (0/0) (0/0) 2 0.1 - - 12o - 5 - 316 - 148 123.3 - 8 0.1 - - 141 - 11 - -. 100.0 90 63.8 53.1 14 0,1 - - 155 - - 17 - - 56.2 71 45.8 38.1 2o 0.1 - -. 165 - - 23 - - 31.6 67 40.6 33.8 26 0.1 - - 167 _ - - 29 - 316 - 195 116.5 - 5, 29 MEAN - - - - 12o.1 (a) TABLE 3.8.4 AMPLITUDE ON THE RECORDER, CR-1274 rabbit no. 1251, 4th strip (a) This value is set as a 100-0/o nicotine contraction (maximum nicotine amplitude).
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REPORT A c!joo/3o17.o9 RL17 (R) B15 STEP NUMBER DING TO CCO ORGAN BATH CONCENTRATTON AMPLITUD_E_ A R TABLE A NORADRE- NALINE (umol/i) REF. SUBST. (umol/1) TEST SUBST. (umol/1) ABS. mm) RELATIVE TO PRECEDING NORADRENALINE AMPLITUDE (0/0) MAXIMUM NICOTINE AMPLITUDE (0/0) 2 0.1 - - 22 -. - 5 - 316 - 48 218.2 - 8 o.i _ - - 27 - - 11 - - 100.0 46 17o.3 94.4 14 0.1 - - 4o - - 17 - - 56.2 46 115.o 63.7 2o 0.1 - - 48 - -. 23 -. - 31.6 29 6o.4 33.5 26 0.1 -. - 61 - - 29 - 316 - 87 142.6 - 5, 29 MEAN - - - - 180.4 (a) TABLE 3.8.5 AMPLITUDE ON THE RECORDER, CR-1274 rabbit no. 1414, 2nd strip (a) This.value is set as a loo-o/o nicotine contraction (maximum nicotine amplitude). zzCsUszooi
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REPORT A o500/3017.09 RL17 (R) B16 N C STEP NUMBER ORGAN BATH CONCENTRATION AMPLITUDE G ~ ACCORDING TO Q TABLE A NORADRE- REF. TEST ABS. RELATIVE TO 0 O NALINE SUBST. SUBST. PRECEDING MAXIMUM cn NORADRENALINE AMPLITUDE NICOTINE AMPLITUDE A ~ (umol/1) (umol/1) (umol/1) (mm) (0/0) (0/0) CD 0 a 0 ~ 2 0.1 43 c 5 - 316 65 151.2 - :3 (a 8 0.1 63 1 1 -. 562.0 73 115.9 87.9 14 0.1 72 a 17 - 316.o 82 113.9 86.4 7 2o 0.1 77 23 - 178.0 84 109. 1 82.7 26 0.1 80 . 29 - 316 90 112.5 5, 29 MEAN 131.9 (a) TABLE 3.8.6 AMPLITUDE ON THE RECORDER, CR-1274 rabbit no. 1414, 4th strip (a) This value is set as a loo-o/o nicotine contraction (maximum nicotine amplitude). zZCsCszoai
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STEP NUMNtR ORGAN BATH CONCENTRATION AMPLITUDE IN%1 TO ACCORD Ti+BLE A NORADRE- NALINE' REF. TEST SUBST. SUBST. ABS. RELATIVE TO PRECEDING NORADRENALINE AMPLITUDE MAXIMUM NICOTINE AMPLITUDE (umol/1) (umol/1) (umol/1) (mm) (0/0) (0/0) 2 0.1 - - 44 - - 5 - 316 - 61 138.6 g o.1 - - 50 - - 11 - - 31.6 1 2.o 1.4 14 0.1 - - 73 - - 17 - - 56.2 29 39.7 28.2_ 2o 0.1 - -. 81 - 23 - - 100.0 87 1o7.4 76.3 26 0.1 - - 91 - -. 29 - 316 - 13o 142.9 - NF; AN 14o.8 (8) TABLE 3.0•7 AMPLITUUd O rabbit tt0. N THE RECORDER, 1254, 2nd strip CR-1274 (a) Thie value is set as a loo-o/o nicotine contr action (maximum nicotine amplitude). EzESCszooT
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0 REPORT A o5oo/3o17.o9 RL17 (R) B18 ® STEP NUMBER ACCORDING TO ORGAN BATH CONCENTRATION AMPLITUDE TABLE A NORADRE-. NALINE (umol/1) REF. SUBST. (umol/1) TEST SUBST. (umol/1) ABS. mm) RELATIVE TO PRECEDING NORADRENALINE AMPLITUDE (o/o) MAXIMUM NICOTINE AMPLITUDE (0/0) 2 0.1 4o - - 5 316 - 63 157.5 8 0.1 - - 44 - - 11 - 178.o 50 113.6 78.1 14 0.1 - - 65 - - 17 - 316.0 57 87.7 6o.3 2o 0.1 - - 71 - - 23 - 562.o 83 116.9 8o.4 26 0.1 84 - 29 316 - 112 133.3 - 5, 29 MEAN - - - - 145.4 (a) TABLE 3.8.8 AMPLITUDE ON THE RECORDER, CR-1274 rabbit no.. 1254,` 4th strip ~ (a) This value is set as a 100-0/o nicotine contraction (maximum nicotine amplitude). vMsUszooi
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STEP NUMBER ORGAN BATH CONCENTRATION AMPLITUDE ORDING TO ACC TABLE A NORADRE- NALINE (umol/1) REF. SUBST. (umol/1) TEST ABS. RELATIVE TO SUBST. PRECEDING NORADRENALINE AMPLITUDE (umol/1) (mm) (0/0) 2 0.1 - - 122 - 5 - 316 -. 1o4 85.2 8 0.1 - - 141 - 11 - - 178.o 53 37.6 14 0.1 - - 171 -. 17 - -. 316.o 124 72.5 2o 0.1 - - 175 -. 23 - - 562.0 166 94.9 26 0.1 - - 176 - 29 - 316 - 153 86.9 TABLE 3.9.1 AMPLITUDE O rabbit no. N THE RECORDER, 1249, 1st strip CR-1766A (a) This value is set as a loo-o/o nicotine contraction (maximum nicotine MAXIMUM NICOTINE AMPLITUDE (0/0) amplitude). s~~sESZOOT
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REPORT A o500/3017.09 RL17 (R) B3 STEP NUMBER ORGAN BATH CONCENTRATION AMPLITUDE ACCORDING TO TABLE A NORADRE-. REF. TEST ABS. RELATIVE TO NALINE SUBST. SUBST. PRECEDING MAXIMUM NORADRENALINE NICOTINE AMPLITUDE AMPLITUDE (umol/1) (umol/1) (umol/i) (mm) (0/0) (0/0) 2 0.1 - - 114 - - 5 - 316 - 154 135.1 - 8 0.1 - - 137 - 11 - - 31.6 3 2.2 1.8 14 0,1 - - 176 - . 17 - - 56.2 26 14.8 11.8 2o 0.1 - - 181 -. - 23 - - 100,0 145 80.1 64.1 2 6 0.1 - -. 176 - .- 29 - 316 - 2o2 114.8 - 5, 29 MEAN - - - - 125.o (a) TABLE 3.9.2 AMPLITUDE ON THE RECORDER, CR-1766A rabbit no. 1429, 3rd strip (a) This value is set as a loo-o/o nicotine contraction (maximum nicotine amplitude). 92C6C6ZOOZ
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REPORT A o5oo/3017.o9 RL17 (R) B4 STEP NUMBER CCORDING TO ORGAN BATH CONCENTRATION AMPLITUDE A TABLE A NORADRE- NALINE (umol/1) REF. SUBST. (umo3/1) TEST SUBST. (umol/1) ABS. r^m) RELATIVE TO PRECEDING NORADRENALINE AMPLITUDE (0/0) MAXIMUM NICOTINE AMPLITUDE (0/0) 2 0.1 - - 71 - 5 - 316 - 93 131.0 8 0.1 - - 86 - 11 - - 562.0 99 115.1 91.9 1 4 0.1 - - 99 - - 17 - 316.0 101 1o2.o 81.5 2o 0.1 - 1o6 - - 23 - - 178.o 74 69.8 55.8 26 0.1 - - 114 - - 29 - 316 - 136 119.3 - 5, 29 MEAN 125.2 (a) TABLE 3.9.3 AMPLITUDE ON THE RECORDER, CR-1766A rabbit no. 1251, 1st strip (a) This value is set as a 100-0/o nicotine contraction (maximum nicotine amplitude). GZUsCszooi
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® REPORT A o5oo/3o17.o9 RL17 (R) B5 ~ STEP NUMBER ORGAN BATH CONCENTRATION ACCORDING TO AMPLITUDE TABLE A NORADRE- REF. TEST ABS. RELATIVE TO NALINE SUBST. SUBST. PRECEDING MAXIMUM NORADRENALINE NICOTINE AMPLITUDE AMPLITUDE (imol/1) (umol/1) (umol/1) (mm) (o/o) (o/o) 2 5 8 11 14 17 2o 23 26 29 5, 9 AN 0.1 - 0.1 - 0.1 - 0.1 - 0.1 - - - 316 - - - - - - - 316 - - - - 100.0 - 56.2 -. 31.6 - - - 115 127 126 61 143 17 161 1 16o 2oi - - 11o.4 - 48.4 - 11.9 - o.62 125.6 117.9 (a) - 41.1 - 10.1 - o.53 TABLE 3.9.4 AMPLITUDE ON THE RECORDER, CR-1766A rabbit no. 1251, 3rd strip (a) This value is set as a loo-o/o nicotine contraction (maximum nicotine amplitude). . OMVCV4QQ r
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0 0 REPORT A o5oo/3o17.o9 RL17 (R) B6 STEP NUMBER ORGAN BAT H CONCENTRATION AMPLITUDE ACCORDING TO _ TABLE A NORADRE- REF. TEST ABS. RELATIVE TO NALINE_ SUBST. SUBST. PRECEDING MAXIMUM NORADRENALINE NICOTINE AMPLITUDE AMPLITUDE (umol/1) (umol/1) (umoi/1) (mm) (0/0) (0/0) 2 0.1 5 8 0._1 11 - 14 0.1 17 - 2o 0.1 23 - 26 0.1 29 - 5, 29 MEAN - TABLE 3.9.5 AMPLITUDE ON THE RECORDER, rabbit no. 1414, 1st strip (a) This value is set as a 38 316 65 171.1 - 46 100.0 23 5o.o 34.2 59 56.2 1 1.7 1.2 64 31.6 0 0 0 70 316 85 121.4 146.3 (a) CR-1766A 1oo-.o/o nicotine contraction (maximum nicotine amplitude). STEP NUt ACCORDIt TAPLE A 5, 29 TA3LE 3. AMPLITtJt rabbit r (a) Tth?c szUsCszooi
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I REPORT A o500/3017.09 RL17 (R) B7 STEP NUMBE.^. ORGAN BATH CONC :NTRAT_ ION AMPLITUDE ACCORDING 'iJ_ TABLE A NORADRE- 1~. '. TEST ABS. RELATIVE TO NALINE SU3ST, SUBST. PRECEDING MAXIMUM NORADRENALINE NICOTINE AMPLITUDE AMPLITUDE (umol/1) (umol/1) (umol/1) (mm) (o/o) (0/0) 2 0.1 -. - 31 - - 5 - 316 - 61 196.8 - 8 0.1 - - 4o - - 11 - - 562.o 63 157.5 85.5 14 0.1 - - 5o - - 17 - - 316.o 57 114.o 61.9 2o 0.1 - - 51 - - 23 - - 178.0 33 64.7 35.1 26 0.1 - - 53 - - 29 - 316 - 91 171.7 - 5, 29 MEAN - - - - 184.3 (a) TABLE 3.9.6 AMPLITUDE ON THE RECORDER, CR-1766A rabbit no. 1414, 3rd strip (a) This value is set as a loo-o/o nicotine contraction (maximum nicotine amplitude). oCESESZOOZ
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I REPORT A o5oo/3o17.o9 RL17 (R) B8 STEP NUMBER ORGAN BATH CONCENTRATION AMPLITUDE RDING TO ACCO TABLE A NORADRE- REF. TEST ABS. RELATIVE TO NALINE SUBST. SUBST. PRECEDING MAXIMUM NORADRENALINE NICOTINE AMPLITUDE AMPLITUDE (umol/1) (umol/1) (umol/1) (mm) (0/0) (0/0) 2 0.1 - - 53 - - 5 - 316 -. 73 137.7 - 8 0.1 - - 63 - - 11 - -. 31.6 0 0 0 14 0.1 - - 85 - - 17 -. - 56.2 3 3.5 2.8 2o 0.1 - -. 89 _ - - 23 - - 100.0 58 65.2 51.5 26 0.1 - - 1o4 - - 29 - 316 - 120 115.4 - 5, 29 MEAN - - - - 126.6 (a) TABLE 3.9.7 AMPLITUDE ON THE RECORDER, CR-176tiA rabbit no. 1254, ist strip (a) This•value is set as a loo-o/o nicotine contraction (maximum nicotine amplitude). ZEC6€6ZOOZ
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b z REPORT A o5oo/3o17.o9 RL17 (R) B9 STEP NUMBER O I G ORGAN BATH CONCENTRATION AMPLITUD_E_ Rll N TO ACC TABLE A NORADRE- REi. TEST ABS. RELATIVE TO NALINE SUBST. SUBST. PRECEDING MAXIMUM NORADRENALINE NICOTINE AMPLITUDE AMPLITUDE (umol/1) (umol/1) (umol/i) (mm) (0/0) (0/0) 2 0.1 5 - 8 0.1 11 - 14 0.1 17 - 2o 0.1 23 - 26 0.1 29 - 5, 29 MEAN - - 316 - - - - - - - 316 - - - - 178.o - 316.o - 562.o - - - 45 - 46 1o2.2 49 - 13 26.5 69 - 18 26.1 78 -. 62 79.5 87 - 92 1o5.7 - 1o4.o ) - - 25.5 -. 25.1 - 76.4 - - TABLE 3.9.8 AMPLITUDE ON THE RECORDE il, CR-1766A rabbit no. 1254, 3rd str ip I (a) This value is set as a loo-o/o nicotine cont raction (maximum nicotine amplitude). zEESESZOOT 2 5 8 11 14 17 2o 23 26 29 5, 29 ME[ TABLE 3.8.: AMPLITUDE ( rabbit no. (a) This va
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I REPORT A o5oo/3o17.o9 RL21 (R) A23 (GD) STEP NUMBER ORGAN BATH CONCENTRATION AMPLITUDE ACCORDING TO TABLE A NORADRE-. REF. TEST ABS. RELATIVE TO NALINE SUBST. SUBST. PRECEDING MAXIMUM NORADRENALINE NICOTINE AMPLITUDE AMPLITUDE (umol/1) (umol/1) (umol/1) (mm) (0/0) (0/0) 2 0.1 - - 91 - - 5 - 316.o - 110 12o.9 - 8 0.1 - - 121 - - 11 - 10.0 - 3 2.5 2.3 14 0.7 - - 142 - - 1? - 31.6 - 1o2 71.8 65.9 2o 0.1 -. - 151 - - 23 - 100.0 - 152 loo.7 92.5 26 0.1 - - 154 - -. 29 - 316.o -. 149 96.8 - 5, 29 MEAN - - - - loB.9 (a) TABLE 3.1o.1 AMPLITUDE ON THE RECORDER, REFERENCE SUBSTANCE rabbit no. 1477, 2nd strip (a) This value is set as a loo-o/o nicotine contraction (maximum nicotine amplitude). Museszooi 5, 29 M TABLE 3.8 AMPLITUDE rabbit no (a) This
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REPORT A o5oo/3o17.o9 RL21 (R) A25 (GD) STEP NUMBER ORGAN BATH CONCENTRATION AMPLITUDE ACCORDING TO TABLE A NORADRE- REF. TEST ABS. RELATIVE TO NALINE_ SUBST. SUBST. PRECEDING MAXIMUM NORADRENALINE NICOTINE AMPLITUDE AMPLITUDE (umol/1) (umol/1) (umol/1) (mm) (0/0) (o/o) 2 5 8 11 14 17 2o 23 26 29 5, 9 AN 0.1 - 0.1 - 0.1 - 0.1 - 0.1 - - - 316.o - 1000.0 - 178o.o - 316o.o - 316.o - -. - - - - - - -. - -. - 9 2 74 116 75 131 61 137 49 144 92 - - 8o.4 - 64:7 - 46.6 - 35.8 - 63.9 72.2 ) - - - 89.6 - 64.5 - 49.6 - - TABLE 3.io.2 AMPLITUDE ON THE RECORDER, REFERENCE SUBSTANCE rabbit no. 1314, 3rd strip (a) This value is set as a loo-o/o nicotine contraction (maximum nicotine amplitude). , 29 M TABLE 3.8 AMPLITUDE rabbit no ( ) This • PUESMzooT
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0 REPORT A o5oo/3oi7.o9 RL21 (R) A26 (GD) 0 STEP NUMBER ORGAN BATH CONCENTRATION AMPLITUDE ACCORDING TO TABLE A NORADRE- REF. TEST ABS. RELATIVE TO NALINE SUBST. SUBST. PRECEDING MAXIMUM NORADRENALINE_ NICOTINE AMPLITUDE AMPLITUDE (umol/1) (umol/1) (umol/1) (mm) (0/0) (0/0) 2 0.1 56 - - 5 - 316.o 20 50.0 - 8 0.1 79 - - 11 - 100.0 35 44.3 1o5.5 14 0.1 94 - - 17 - 178.o 38 4o.4 96.2 20 0.1 100 - - 23 - 562.0 3o 30.0 71.4 26 0.1 1o6 - - 29 - 316.o 36 34.0 - 5, 29 MEAN - - - - 42.0 (a) TABLE 3.1o.3 AMPLITUDE ON THE RECORDER, REFERENCE SUBSTANCE rabbit no. 1485, 2nd strip (a) This value is set as a loo-o/o nicotine contraction (maximum nicotine amplitude). ..'74EG(.VZ00 Y 5, 29 MI TABLE 3.8. AMPLITUDE rabbit no. (a) This %
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STEP NUMBER - ACCORDING TO TABLE A ORGAN BATH CONCENTRATION AMPLITUDE NORADRE- NALINE umol/1) REF. TEST SUBST. SUBST. - (umol/1) (umol/1) ABS._ mm) RELATIVE TO PRECEDING NORADRENALINE AMPLITUDE (o/o) MAXIMUM NICOTINE AMPLITUDE (0/0) 0.1 1o2 316.o 62 60.8 - 0.1 126 10.0 9 7.1 12.4 0.1 144 17.8 34 23.6 41.1 0.1 153 31.6 66 43.1 75.1 0.1 154 316.o 83 53.9 - TABLE 3.1o.4 AMPLITUDE ON THE RECORDER, REFERENCE SUBSTANCE rabbit no. 1485, 3rd strip (a) This value is set as a 100-0/o nicotine contraction (maximum nicotine amplitude). - 9EUsESZOOT REPORT A STEP NUME ACCORDIN( TABLE A 2 5 8 11 14 17 2o 23 26 29 29 M TABLE 3.8 AMPLITUDE rabbit no (a) This
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REPORT A o500/3o17.o9 0 RL21 (R) A28 (GD) ~ STEP NUMBER ORGAN BATH CONCENTRATION AMPLITUDE ACCORDING TO TABLE A NORADRE- REF. TEST ABS. RELATIVE TO NALINE SUBST. SUBST. PRECEDING MAXIMUM NORADRENALINE_ NICOTINE AMPLITUDE AMPLITUDE (umol/1) (urnol/1) (umol/1) (mm) (0/0) (0/0) 2 5 8 11 14 17 2o 23 26 29 5, 9 A 0.1 - 0.1 - 0.1 - 0.1 -. 0.1 - N - - 316.o - 1000.0 - 178o.o - 316o.o - 316.0 - - -. - - - - - - - - - 69 17 97 17 116 13 121 10 123 28 - - 24.6 - 17.5 -. 11.2 - 8.2_ - 22.7 23.7 (a) - - - 73.8 - 47.3 - 34.6 - - TABLE 3.1o .5 AMPLITUDE O rabbit no. N THE RECORDER, 1485, 4th strip REFERENCE SUBSTANCE (a) This value is set as a loo-o/o nicotine contraction (maximum nicotine amplitude). TABLE 3. AMPLITUD rabbit n (a) This 4CCsCszooT
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REPORT A c STEP NUMBER ORGAN BATH CONCENTRATION AMPLITUDE CCORDING TO A TABLE A NORADRE- REF. TEST ABS. RELATIVE TO NALINE SUBST. SUBST. PRECEDING MAXIMUM NORADRENALINE NICOTINE AMPLITUDE AMPLITUDE (umol/1) (umol/1) (umoi/3) (mm) (0/0) (o/o) 0.1 - - 78 - - 316.o - 83 1o6.4 0.1 - - 99 - - 56.2 - 78 78.8 80.1 0.1 -. - 106 - - 31.6 - 65 61.3 6 2`. 3 0.1 - - 114 - - 17.8 - 22 19.3 19.6 0.1 - - 115 - - 316.o .. 1o4 9o.4 TABLE 3.10.6 AMPLITUDE ON THE RECORDER, REFERENCE SUBSTANCE rabbit no. 13o8, 2nd strip STEP NUMBE ACCORDING TABLE A 2 5 8 11 14 17 2o 23 26 29 5, 29 ME TABLE 3.8. AMPLITUDE rabbit no. (a) This v (a) This value is set as a 1oo-o/o nicotine contraction (maximum nicotine amplitude). BMGM00Z
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d s REPORT A o5oo/3 o17.o9 RL21 (R) A3c (GD) . z m REPORT A o5 T O S N C C:' STEP NUMBER STEP NUMBER ORGAN BATH CONCENTRATION AMPLITUDE Q ACCORDING T ACCORDING TO 0 TABLE A TABLE A NORADRE- REF TEST ABS RELATIVE TO . . 0 NALINE SUBST. SUBST. PRECEDING NORADRENALINE AMPLITUDE MAXIMUM NICOTINE AMPLITUDE cn n ~ cD (umol/1) (umol/1) (umol/1) (mm) (0/0) (0/0) ~ 0 ~ 2 2 0.1 - - 65 - - C =1 5 5 - 3i6.o - 59 90.8 - ca 8 8 1 - - 77 0 - - 11 . - 562.o - 62 80.5 98.4 7* 11 14 14 1 - - 83 0 - - . ~ 17 17 - 1000.0 - 55 66.3 81.1 2o 2o 0.1 - - 87 -. - 23 23 - 1780.0 - 47 54.o 66.o 26 26 o.1 - - 88 - - 29 29 -. 316.o - 64 72.7 - 5, 29 MEAi 5, 29 MEAN - - - - 81.8 (a) TABLE 3.1o.7 AMPLITUDE ON THE RECORDER, REFERENCE SUBSTANCE rabbit no. 13o8, 4th strip (a) This value is set as a 100-0/o nicotine contraction (maximum nicotine amplitude). GCUsCszooT TABLE 3.9.1 AMPLITUDE 01 rabbit no. (a) This va:
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STEP NUMBER ORGAN BATH CONCENTRATION AMPLITUDE ACCORDING TO TABLE A NORADRE- NALINE (umol/1) REF. TEST SUBST. SUBST. (umol/1) (umol/1) ABS. mm) RELATIVE TO PRECEDING NORADRENALINE AMPLITUDE (0/0) MAXIMUM NICOTINE AMPLITUDE (0/0) 2 0.1 31 5 - 316,o 2o 64.5 - 8 0.1 44 11 - 1000.0 21 47.7 83.8 14 0.1 55 1 7 -. 178o.o 19 34.5 6o.6 2o 0.1 61 23 - 316o.o 16 26.2 46.o 26 0.1 69 29 - 316.o 34 49.3 - 5, 29 MEAN - 56.9 (a) - TABLE 3.1o.8 AMPLITUDE ON THE RECORDER, REFERENCE SUBSTANCE rabbit no. 1479, 1st strip (a) This value is set as a 100-0/o nicotine contraction (maximum nicotine amplitude). O YeG(. V CaIU T REPORT A o5 STEP NUMBER ACCORDING 7 TABLE A 0 =r 2 c ~ 5 cn 8 11 7C 14 oc 5' 17 2o 23 26 29 5, 29 MEA TABLE 3.9.2 AMPLITUDE G rabbit no. (a) This va
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STEP NUMBER ORGAN BATH CONCENTRATION AMPLITUDE ACCORDING TO TABLE A NORADRE- NALINE REF. SUBST. TEST SUBST. ABS. RELATIVE TO PRECEDING NORADRENALINE AMPLITUDE MAXIMUM NICOTINE AMPLITUDE (umol/1) (umol/1) (umol/].) (mm) (0/0) (0/0) 2 0.1 - -. 8 2 - - 5 - 316.o - 80 97.6 - 8 0.1 -. - 95 - - 11 - 100.0 - 94 98.9 112.9 14 0.1 - 111 - 17 - 178.o - 99 89.2 101.8 2o 0.1 - - 114 - 23 - 562.o - 92 8o.7 92.1 26 0.1 - - 125 _ - 29 - 316.o 97 77.6 - 5, 29 MEAN - - - - 87.6 (a) TABLE 3.1o.9 AMPLITUDE ON THE RECORDER, REFERENCE SUBSTANCE rabbit no. 1479, 3rd strip (a) This value is set as a ioo-o/o :sicotine contraction (maximum nicotine amplitude). _- iVUs€sZooi REPORT A
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REPORT A , STEP NUMBER ORGAN BATH ACCORDING TO TABLE A NORADRE- NALINE (umol/1) 2 0.1 S - 8 0.1 11 - 14 0.1 17 - 2o 0.1 23 - 26 0.1 29 -. 5, 29 MEAN - TABLE 3.1o.lo AMPLITUDE ON THE RECORDER, rabbit no. 1!79, 4th strip CONCENTRATION AMPLITUDE REF. SUBST. TEST SUBST. ABS. RELATIVE TO PRECEDING NORADRENALINE AMPLITUDE MAXIMUM NICOTINE AMPLITUDE (umol/i) (umol/1) (mm) (0/0) (0/0) - - 61 - - 316.o - 49 8o.3 - - - 79 - - 10.0 -. 16 20.3 26.7 - - 93 - - 17.8 - 38 4o.9 53.8 - - loo - - 31.6 - 75 75.o 98.7 - - 1o6 - - 316.o - 76 71.7 - - - - 76.o (a) REFERENCE SUBSTANCE (a) This value is set as a loo-o/o nicotine contraction (maximum nicotine amplitude). %VCsCszooT STEP NUMB ACCORDING TABLE A 2 5 8 11 14 17 2o 23 26 29 5, 29 Mi TABLE 3.9 AMPLITUDE rabbit no (a) This ,
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b REPORT A o5oo/3o17.o9 RL21 (R) B15 STEP NUMBER ACCORDING TO ORGAN BATH CONCENTRATION (a) AMPLITUDE TABLE A NORADRE- NALINE (umol/1) REF. TEST SUBST. SUBST. (umol/1) (umol/1) ABS. mm) RELATIVE TO PRECEDING NORADRENALINE AMPLITUDE (o/o) MAXIMUM NICOTINE AMPLITUDE (o/o) 2 0.1 45 - - 5 - 316.o 8o 177.8 - 8 0.1 5 8 - -. 11 - 562.0 90 155.2 92.7 14 0.1 68 - - 17 - 1000.0 96 141.2 84.3 2o 0.1 7o - - 23 - 316.o 110 157.1 - 26 - 29 - 5, 23 MEAN - - - - 167.5 (b) TABLE 3.1o.11 AMPLITUDE ON THE RECORDER, REFERENCE SUBSTANCE rabbit no. 122o, 1st strip (a) concentrations differ from that given in TABLE A (b) This value is set as a loo-o/o nicotine contraction (maximum nicotine amplitude). V vEGlaGZoo . TABLE 3.9.`_ AMPLITUDE C rabbit no. (a) This va
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REPORT A o500/3017.09 RL21 (R) B16 z @ 0 5 N C STEP NUMBER ACCORDING TO ORGAN BATH CONCENTRATION (a) AMPLITUDE C? Q 0 TABLE A NORADRE- REF. TEST ABS. RELATIVE TO 0 NALINE SUBST. SUBST. PRECEDING MAXIMUM 9y NORADRENALINE AMPLITUDE NICOTINE AMPLITUDE n a CD "T1 (umol/1) (umol/1) (umol/1) (mm) (0/0) (0/0) 0 n ~ 2 0.1 3 5 -. - C ~ 5 - 316.o 57 162.9 - ~ 8 0.1 43 - - 11 - 178.o 72 167.4 101.0 a 14 0.1 49 - - 3 17 - 100.0 65 132.7 80.1 2o 0.1 54 - - 23 - 316.o 91 168.5 - 26 - 29 - 5, 23 MEAN - - - - 165.7 (b) TABLE 3.1o.12 AMPLITUDE ON THE RECORDER, REFERENCE SUBSTANCE rabbit no. 122o, 2nd strip (a) concentrations differ from that given in TABLE A (b) This value is set as a 100-.0/o nicotine contraction (maximum nicotine amplitude). REPORT A o`_ STEP NUMBEY ACCORDING : TABLE A 2 5 8 11 14 17 2o 23 26 29 5, 29 MEA TABLE 3.9.6 AMPLITUDE 0 rabbit no. (a) This va VVE6E6z00Z
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REPORT A o500/3o17.o9 RL21 (R) B17 STEP NUMBER ORGAN BATH CONCENTRATION (a) AMPLITUDE ACCORDING TO TABLE A NORADRE- REF. TEST ABS. RELATIVE TO NALINE SUBST. SUBST. PRECEDING MAXIMUM NORADRENALINE NICOTINE AMPLITUDE AMPLITUDE (umol/1) (umol/1) (umol/1) (mm) (0/0) (0/0) 2 5 8 11 14 17 2o 23 26 29 5, 3 AN 0.1 - - -. 316.o - 0.1 - - -. 56.2 - 0.1 - - -. 31.6 - 0.1 - - - 316.o - - - - - - - - - - 21 60 28 69 32 59 35 88 - - - - 285.7 - 246.4 184.4 - 251.4 - - 268.6 ) - - - 91.7 68.7 - - - - TABLE 3.to.13 AMPLITUDE ON THE RECORDER, REFERENCE SUBSTANCE rabbit no. 122o, 3rd strip (a) concentrations differ from that given in TABLE A (b) This value is set as a 100-0/o nicotine contraction (maximum nicotine amplitude). z ® 2 REPORT A c ~ O ~ w E c N STEP NUMBI IU o 0 TABLE A O ~ w 0 :r CD ~ 0 ~ 0 ~T ® 2 a 14 :3 17 2o 23 26 29 5, 29 ME TABLE 3.9. AMPLITUDE rabbit no. (a) This v SKGE6Z00Z
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} REPORT A o500/3017.09 RL21 (R) BIB STEP NUMBER ORGAN BATH CONCENTRATION (a) AMPLITUDE ACCORDING TO TABLE A NORADRE- REF. TEST ABS. RELATIVE TO NALINE SUBST. SUBST. PRECEDING MAXIMUM (umol/1) (umol/1) (umol/1) (m.m) NORADRENALINE AMPLITUDE (o/o) NICOTINE AMPLITUDE (0/0) 2 0.1 - - 45 - - 5 - 316.o - 86 191.1 - 8 0.1 - - 53 - - 11 - 1780.0 - 89 167.9 91.3 14 0.1 - - 63 - - 17 - 316o.o - 89 141.3 76.9 20 0.1 - - 68 - - 23 - 316.o - 120 176.5 - 26 :Q 5, 23 MEAN - - - - 183.8 (b) TABLE 3.1o.14 AMPLITUDE ON THE RECORDER, REFERENCE SUBSTANCE rabbit no. 122o, 4th strip (a) concentrations differ from that given •in TABLE A (b) This value is set as a loo-o/o nicotine cuntraction (maximum nicotine amplitude). 9PE6E0200T
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REPORT A o5oo/3o17.L,9 RL21 (R) B19 STEP NUMBER ORGAN BATH CONCENTRATION AMPLITUDE CCORDING TO A TABLE A NORADRE- REF. TEST ABS. RELATIVE TO NALINE SUBST. SUBST. PRECEDING MAXIMUM NORADRENALINE NICOTINE AMPLITUDE AMPLITUDE (umol/1) (umoi/i) (umol,'1) (mm) (o/o) (0/0) 2 5 8 11 14 17 2o 23 26 29 5, 9 AN 0.1 - 0.1 - 0.1 - 0.1 - 0.1 - - 316.o 1000.0 178o.o 316o.o 316.o - - 110 1o4 129 131 13o 137 143 139 152 153 - - 94.5 - 101.6 - 1o5.4 - 97.2 - loo.7 97.6 ) - - - 1o4.1 - 108.0 - 99.6 - - TABLE 3.1o.15 AMPLITUDE ON THE RECORDER, REFERENCE SUBSTANCE rabbit no. 12o8, 1st strip (a) This value is set as a loo-o/o nicotine contraction (maximum nicotine amplitude). 5, 29 MEAN TABLE 3.1o. AMPLITUDE ON rabbit no. 1. (a) This valt 4VesCszooz
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I ® ORGAN BATH CONCENTRATION NORADRE- REF. TEST NALINE SUBST. SUBST. (umol/1) (umol/1) (umol/1) 5, 29 MEAN - Q AMPLIT!;DE ABS. RELATIVE TO PRECEDING MAXIMUM NORADRENALINE NICOTINE AMPLITUDE AMPLITUDE (mm) (0/0) (0/0) 97 - - 316.o 99 io2. 1 - 122 - - 100.0 118 96.7 82.7 127 - - 178.o 165 129.9 111.1 133 - - 562.o 184 138.3 118.3 139 - - 316.o 183 131.7 - - - - 116.9 (a) TABLE 3.1o.16 AMPLITUDE ON THE RECORDER, REFERENCE SUBSTANCE rabbit no.. 12o8, 2nd strip (4) This value is set as a 100-0/o nicotine contraction (maximum nicotine amplitude). eVESCszooT ,~~ ~~cr + sx~ _s
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® REPORT A o500/3017.09 RL21 (R) B21 STEP NUMBER ORGAN BAT H CONCENTRATION AMPLITUDE ACCORDING TO - TABLE A NORADRE-. NALINE REF. SUBST. TEST SUBST. ABS. RELATIVE TO PRECEDING NORADRENALINE_ AMPLITUDE MAXIMUM NICOTINE AMPLITUDE (umol/1) (umol/1) (umol/1) (mm) (0/0) (0/0) 2 0.1 - - 76 - 5 - 316.o - 45 59.2 8 0.1 - - 92 - 11 -. 17.8 - 17 18.5 2o.3 14 0.1 - . 98 - 17 - 31.6 - 31 31.6 34.6 2o 0.1 - .. 101 - 23 - 56.2 - 95 94.1 io3.2 26 0.1 -. - 1o4 - 29 - 316.o - 128 123.1 5, 29 MEAN 91.2 (a) TABLE 3.1o.17 AMPLITUDE ON THE RECORDER , REFERENCE SUBSTANCE rabbit no. 12o8, 3rd stri p (a) This value is set as a loo-o/o nicotine contraction (maximum nicotine amplitude). V Y(.V4VMOT 5, 29 ME TABLE 3.1 AMPLITUDE rabbit no. (a) This v•
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0 REPORT A o5oo/3o17.o9 RL21 (R) B22 ® STEP NUMBER ACCORDING TO ORGAN BAT H CONCENTRATION AMPLITUDE TABLE A NORADRE- NALINE REF. TEST SUBST. SUBST. ABS. RELATIVE TO PRECEDING NORADRENALINE AMPLITUDE MAXIMUM NICOTINE AMPLITUDE (umul/1) (umol/1) (umol/1) (mm) (0/0) (0/0) 2 0.1 1o3 5 8 11 14 17 2o 23 26 29 5, 9 AN - 0.1 - 0.1 - 0.1 - 0.1 - 316.o 10.0 100..0 1000.0 316.o 92 123 1 133 135 136 168 143 162 89.2 0.81 lol.5 123.5 113.3 lol.3 ) - o.8 loo.2 121.9 - TABLE 3.10.18 AMPLITUDE ON THE RECORDER , REFERENCE SUBSTANCE rabbit no.. 12o8, 4th stri p (a) This value is set as a 100-0/o nicotine contraction (maximum nicotine amplitude). REPORT A 5, 29 TABLE 3. AMPLITUDE rabbit nc (a) This 0SUGCV4QQ M
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® REPORT A o5oo/3o17.o9 RL21 (R) B23 0 STEP NUMBER ORGAN BATH CONCENTRATION AMPLITUDE ACCORDING TO TABLE A NORADRE- REF. TEST ABS. RELATIVE TO NALINE SUBST. SUBST. PRECEDING MAXIMUM NORADRENALINE NICOTINE AMPLITUDE ANPLITUDE (umol/1) (umol/1) (umol/1) (mm) (0/0) (0/0) z D7 ~ O ~ N E aEPORT ; ~` STEP NUk a_ ACCORD_ID 0 TABLE A O ~ ~ =r CD ~ 0 2 0.1 - - 73 - - c ~ 2 5 5 - 316 o - 65 89.0 - ~ 8 0 1 . - - 85 - - 8 . . 11 11 - 178.o - 75 88.3 87.3_ ~ a 14 14 0 1 - - 90 - - _ . ~ 17 17 - 100.0 -. 58 64.4 63.6 2o 2o 0 1 - - 95 - - . 23 23 - 56.2 - 77 81.1 8o.1 26 26 0 1 - - 98 - - . 29 29 -. 316.o - 111 113.3 - 5, 29 5, 29 MEAN - - - - lol.2 (a) TABLE 3 TABLE 3..io.19 AMPLITUDE ON THE RECORDE R, REFERENCE SUBSTANCE AMPLITUD rabbit no. 1411, 1st str ip rabbit n (a) This value is set as a loo-o/o nicotine contraction (maximum nicotine amplitude). (a) This isEScszooti
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b ® REPORT A o500/3017.09 RL21 (R) B24 0 STEP NUMBER ORGAN BATH CONCENTRATION AMPLITUDE ACCORDING TO a TABLE A NORADRE- REF. TEST ABS. RELATIVE TO R. NALINE SUBST. SUBST. PRECEDING MAXIMUM NORADRENALINE NICOTINE Yi AMPLITUDE AMPLITUDE In (umol/1) (umol/1) (umol/1) (mm) (0/0) (0/0) 2 0.1 - - 29 - - 5 - 316.o - 37 127.6 - 8 0.1 - - 37 - - 11 - 31.6 - 15 40.5 29.9 14 0.1 - - 51 - - 17 - 17.8 - 33 64.7 47.8 2o 0.1 - - 57 - - 23 - 10.0 - 0 0 0 26 0.1 - - 65 - - 29 - 316.o - 93 143.1 - 5, 29 MEAN - - - - 135.4 (a) TABLE 3.1o,2o AMPLITUDE ON THE RECORDER, REFERENCE SUBSTANCE rabbit no. 1411, 2nd strip (a) This value is set as a loo-o/o nicotine contraction (maximum nicotine amplitude). :'~r~.:. - .. ~ , . ~ . ..... .:.~w: _~~.r~:i ~r<'i.~ ~ t :t~i;~--::~.xA •~r':. ~xi +~ i?~.5+aH5, ,>>+'~ ~~~~UM0T ® :~:•L,S. _. , .. ..:...y.r,e".~. : t.:r''~:'Y.;,rAw,;;+vae%y,yr;~::; REPORT A c STEP NUME}f ACCORDING TABLE A 2 5 8 11 14 17 2o 23 26 29 5, 29 ME TABLE 3.1 AMPLITUDE rabbit no. (a) This v
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0 a z REPORT A o500/3017.09 RL21 (R) B25 ® STEP NUMBER ORGAN BATH CONCENTRATION AMPLITUDE ACCORDING TO TABLE A NORADRE- REF. TEST ABS. RELATIVE TO NALINE SUBST. SUBST. PRECEDING MAXIMUM NORADRENALINE NICOTINE AMPLITUDE AMPLITUDE (umol/1) (umol/1) (u:nol/1) (mm) (o/o) (0/0) 2 5 8 11 14 17 2o 23 26 29 5, 9 E 0.1 - 0.1 -. 0.1 - 0.1 - 0.1 - AN - - 316.o - 178o.o - 1000.0 - 316o.o - 316.o - - - - - -. - - - - - - 42 58 59 69 7o 81 72 94 78 113 - - 138.1. - 116.9 - 115.7 - 13o.6 - 144.9 141.5 ) - - - 82.6 - 81.8 - 92.3 - - TABLE 3.1 o.21 AMPLITUDE rabbit no. UN THE RECORDER, 141i, 3rd strip REFERENCE SUBSTANCE (a) This value is set as a 100-0/o nicotine contraction (maximum nicotine amplitude ~S~SE6~OOZ 1 ,,
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I STEP NUMBER ORGAN BATH CONCENTRATION AMPLITUDE ACCORDING TO TABLE A NORADRE- REF. TEST ABS. RELATIVE TO NALINE SUBST. SUBST. PRECEDING MAXIMUM NORADRENALINE NICOTINE AMPLITUDE AMPLITUDE (umol/1) (umol/1) (umol/1) (mm) (0/0) (o/o) 2 0.1 - 21 _ - 5 - 316.o 49 233.3 - 8 0.1 - 26 - - 11 - 178o.o 49 188.5 92.9 14 0.1 - 36 - - 17 - 178.o 69 191.7 94.5 2o 0.1 - 2 9 - -. 23 - 17.8 46 117.9 58.1 26 0.1 - 47 - - 29 - 316.0 81 172.4 - 5, 29 MEAN 2o2.9 (a) TABLE 3.10.22 AMPLITUDE ON THE RECORDER, REFERENCE SUBSTANCE rabbit no. 1411, 4th strip (a) This value is set as a 100-0/o nicotine contraction (maximum nicotine amplitude). ® wo'~0t~gbow ~A V9EGEGZooT 2 5 8 11 14 17 2o 23 26 29 5, 29 TABLE AMPLITU rabbit (a) Thi L
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b 0 ~ REPORT A o5oo/3o17.o9 RL21 (R) B27 4) STEP NUMBER CO NG O ORGAN BATH CONCENTRATION AMPLITUDE RDI T AC TABLE A NORADRE- NALINE umol/1) REF. TEST SUBST. SUBST. - - (umol/1) (umol/1) ABS. mm) RELATIVE TO PRECEDING NORADRENALINE AMPLITUDE (0/0) MAXIMUM NICOTINE AMPLITUDE (0/0) 2 0.1 - - 34 - - 5 - 316.o - 37 108 .8 - 8 0.1 - - 41 _ - - 11 - 31.6 - 9 22.0 15.9 14 0.1 - - 51 - - 17 - 17.8 - 29 56.9 41.2 2o 0.1 - - 62 - -. 23 - 10.0 - 0 0 0 26 0.1 - - 73 - - 29 - 316.o - 122 167.1 - 5, 29 MEAN - - - - 138.o (a) I TABLE 3.io.23 AMPLITUDE ON THE RECORDER, REFERENCE SUBSTANCE rabbit no. 1257, 2nd strip (a) This value is set as a loo-o/o nicotine contraction (maximum nicotine amplitude). SsUsUGWoT
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0 REPORT A o500/3017.09 Rl'.21 (R) B28 0 STEP NUMBER ORGAN BATH CONCENTRATION AMPLITUDE ACCORDING TO TABLE A NORADRE- REF. TEST ABS. RELATIVE TO NALINE SUBST. SUBST. PRECEDING MAXIMUM NORADRENALINC NICOTINE AMPLITUDE AMPLITUDE (umol/1) (umol/1) (umol/1) (mm) (0/0) (0/0) 2 0.1 - - 25 - - 5 - 316.o - 34 136.o 8 0.1 - - 34 - - 11 - 178o.o - 41 12o.6 81.3 14 0.1 - - 4o - - 17 - 1000.0 - 43 1o7.5 72.5 2o 0.1 - - 43 - 23 - 562.o - 64 148.8 loo.3 26 0.1 - - 43 - - 29 - 316.o - 69 16o.5 - 5, 29 MEAN - - - - 148.3 (a) TABLE 3.1o.24 AMPLITUDE ON THE RECORDER, REFERENCE SUBSTANCE rabbit no. 1257, 3rd strip (a) This value is set as a loo-o/o nicotine contrac;tion (maximum nicotine amplitude). 9sC6ESZOOZ REPORT A 5, 29 M[ TABLE 3.1 AMPLITUDE rabbit no. (a) This ti
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b 0 o REPORT A o5oo/3o17.o9 RL21 (R) B29 ® STEP NUMBER ACCORDING_ TO ORGAN BAT H CONCENTRATION AMPLITUDE TABLE A NORADRE- NALINE REF. TEST SUBST. SUBST. ABS. RELATIVE TO PRECEDING NORADRENALINE AMPLITUDE MAXIMUM NICOTINE AMPLITUDE (umol/1) (umol/1) (umol/1) (mm) (0/0) (0/0) 2 0.1 111 5 - 316.o 1o5 94.6 - 8 0.1 12o 11 - 56.2 100 83.3 81.3 14 0.1 1o5 17 - 100.0 109 1o3.8 lol.4 2o 0.1 116 2 3 - 17a.o 121 104..°, 101.9 26 1 0. 99 29 . - 316.0 109 110.1 - 5, 29 MEAN - - - - io2.4 (a) TABLE 3.1o.25 AMPLITUDE ON THE RECORDE R, REFERENCE SUBSTANCE rabbit no. 1267, ;rd str ip (a) This value is set as a 100-0/o nicotine contraction (maximum nicotine amplitude). 4sCsCszooi Z ® a c:' ~v A w a 5 REPORT A o5oc STEP NUMBER ACCORDING TO TABLE A
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4 0 Z m REPORT A o 11 ~ 7 y C G STEP NUMBEI STEP NUMBER ORGAN BATH CONCENTRATION AMPLITUD_E_ 1 ACCORDING ' ACCORDING TO O TABLE A TABLE A NORADRE- REF. TEST ABS. RELATIVE TO 0 NALINE SUBST. SUBST. PRECEDING NORADRENALINE AMPLITUDE MAXIMUM NICOTINE AMPLITUDE Q ~'i =r (D (umol/1) (umol/1) (umol/1) (mm) (0/0) (0/0) "T1 0 ~ 0 =r 2 0.1 - - 154 - - C ~ 2 5 5 - 316 o - 153 4 99 - ~ 8 0.1 . - . - 166 . - - 8 11 11 - 10.0 - 11 6.6 5.8 X 0- 14 14 0.1 - - 142 - - ~ 17 17 - 17.8 - 58 4o.? 35.9 2o 2o 0.1 - - 164 - - 23 23 - 31.6 - 142 86.6 76.2 26 26 0.1 - - 137 - - 29 29 -. 316.0 - 175 127.7 - 5, 23 MEF 5, 29 MEAN - -- - - 113.6 %a) TABLE 3.1o.26 AMPLITUDE ON THE RECORDER, RL'ERENCE SUBSTANCE rabbit no. 1267, 4th strip (a) This value is set as a loo-o/o nicotine contraction (maximum nicotine amplitude). TABLE 3.1c AMPLITUDE C rabbit no. (a) concent (b) This va SsCsUszooi
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0 REPORT A o500/3017.09 RL53 (R) Al 0 z W ® REPORT A o` 0 5 y C STEP NUMBER ORGAN BP.TH CONCENTRATION AMPLITUDE STEP NUMBEI ACCORDING TO Q 0 ACCORDING 9 TABLE A NORADRU- REF. TEST ABS. RELATIVE TO 0 TABLE A NALINE SUBST. SUBST. PRECEDING NORADRENALINE MAXIMUM NICOTINE tn co 0 AMPLITUDE AMPLITUDE S CD 'T1 (umol/1) (umol/1) (umol/1) (mm) (0/0) (o/o) 0 ~ 2 0 1 _ - 108 - - A =r C 2 5 . - 316.o - 12o 111.1 - 5 U3 5 8 o.1 - 106 - -- 8 11 - 562 o - 131 123 6 103 7 A 11 14 . 0.1 - - . 118 - . - o. _ 14 17 - 100> .G - 138 116.9 98.1 3 17 2o . . 0.1 - - 121 - - 2o 23 - 178o.o - 132 109.1 91.5 23 26 0.1 - - 128 -. - 26 29 - 316.0 - 163 127.3 - 29 5, 29 ME AN 119.2 (a) 5, 23 MEA TABLE 3.1 o.27 TABLE 3.10 AMPLITUDE rabbit no. ON THE RECORDER, REFERENCE SUBSTANCE 1269, 1st strip AMPLITUDE 0 rabbit no. (a) This value is set as a 100-0/o nicotine contraction (maximum nicotine amplitude). (a) concent (b) This va ssUsESZOOT
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I 0 REPORT A o5oo/3o17.o9 RL53 (R) A2 0 REPORT A ~ ac G; ' STEP NUMB STEP NUMBER ORGAN BAT H CONCENTRATION AMPLITUDE r_t ~ AGGVnULlvla ACCORDING TO o 1 TABLE A TABLE A NORADRE- NALINE REF. SUBST. TEST SUBST. ABS. RELATIVE TO PRECEDING MAXIMUM 0 ca N NORADRENALINE AMPLITUDE NICOTINE AMPLITUDE 0 cSD (umol/1) (umol/1) (umol/1) (mm) (0/0) (0/0) 0 ~ n 3 0 2 2 0.1 - - 108 - - 5 2 5 5 - 316.o -. 138 127.8 - .. . 8 8 0.1 - - 113 - - 11 11 - 10.0 - 15 13.3 9.9 a 14 14 0.1 - - 131 - - ~ 17 17 - 17.8 - 78 59.5 44.4 2o 2o 0.1 - -. 137 - - 23 23 - 31.6 - 157 114.6 8_5.5_ 26 26 0.1 - - 134 - - .a 29 -. 316.0 - 188 14o.o - 5, 23 MI 5, 29 MEAN - - - - 134.1 (a) i TABLE 3." TABLE 3 1o 28 . . AMPLITUDE ON THE RECORDER, REFERENCE SUBSTANCE rabbit no. 1269, 2nd strip AMPLITUDE rabbit no. (a) This value is set as a loo-o/o nicotine contraction (maximum nicotine amplitude). (a) concer (b) This . 1 -1 o9EsESZOOZ
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® o REPORT A o500/3o17.o9 RL53 (R) A3 REPORT A c ~ ~ ~ STEP NUMBER ORGAN BAT H CONCENTRATION AMPLITUDE C' STEP NUMBI ACCORDING TO a ~ ACCORDING TABLE A NORADRE-. REF. TEST ABS. RELATIVE TO O TABLE A NALINE SUBST. SUBST. PRECEDING NORADRENALINE MAXIMUM NICOTINE ~ A AMPLITUDE AMPLITUDE ~ :~ CD ~ ~+. (umol/1) (umol/1) (umol/1) (mm) (o/o) (o/o) 0 a w la:; n 2 0.1 ' - - 81 - - c 2 5 - 316.o -. 88 1o8.6 - 8 0.1 - - 91 - - 11 - 10.0 - 1 1.1 0.99 ~ 11 :~. 14 0.1 - 95 - - a 14 17 - 17.8 . - 10 10.5 9.4 ~ 17 2o 0.1 1 i 1 - - 2o 23 - .. 31.6 .. - 37 33.3 29.9 23 2 6 0.1 -. -. 9 8 - - 26 29 - 316.o - 112 114.3 - 29 5, 29 MEAN - - - - 111.5 (a) 5, 29 ME I TABLE 3.1o.29 TABLE 3.1 AMPLITUDE ON THE RECORDER , REFERENCE SUBSTANCE AMPLITUDE rabbit no. 127o, 3rd stri p rabbit no. (a) This value is set as a 100-0/o nicotine contraction (maximum nicotine amplitude). (a) This v ~' ' .. . . . .. ,~..~, ~~ TsesMooT 0 (1
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® h:~PORT A o500/3017.09 RL53 (R) A4 ® STEP NUMBER ORGAN BATH CONCENTRATION AMPLITUDE_ ACCORDING TO TABLE A NORADRE- REF. TEST ABS. RELATIVE TO NALINE SUBST. SUBST. PRECEDING MAXIMUM NORADRENALINE NICOTINE AMPLITUDE AMPLITUDE (umol/1) (umol/1) (umol/1) (mm) (o/o) (0/0) 2 5 8 11 14 17 20 23 26 29 5, 9 E 0.1 - - - 316.o - 0.1 - - - 56.2 - 0.1 - - - 100.0 - 0.1 - - - 178.o - 0.1 - - - 316.0 - AN - - - 77 90 86 54 92 84 92 113 90 125 - - 116.9 - 62.8 - 91.3 - 122.8 - 138.9 127.9 ) - - -. 49.1 - 71.4 - 96.o _ - TABLE 3.1 o.3o AMPLITUDE rabbit no. ON THE RECORDER, REFERENCE RUBSTANCE 127o, 4th strip (a) This value is set as a loo-o/o nicotine contrjction (maximum nicotine amplitude). zsESESZOOT REPORT A o STEP NUMBEI ACCORDING ' TABLE A 2 S 8 11 14 17 2o 23 26 29 5, 29 MEt
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0 RERORT A o500/3o17.o9 RL21 (R) B9 REPORT A ~ N . CONCENfRATICN (tmiol/1) L1ATA C FREx1 c U 10 17.8 31.6 56.2 100 178 316 562 loo0 178o 316o TABLE : Q STEP N ME ACCORDINC 0 TABLE A 0 o - 0 - o - - - 3.1.1 Q o - 0 - 0 - - - 3.1.2 f/1 n o - 0 - 0 - - - 3.1.3 S CD 0 MEAN - 0 - o - 0 N RSD (O/O) - 0 N - 3 - 3 -. 3 S c 2 3 5 co 8 11 TABLE 4.1 ~ os ~ 14 17 CONTRACTION RELATIVE TO MAXIMUM NICOTINE OONTRAC'TION (%), CR-14o8 2o 23 26 29 5, 29 M TABLE 3. AMPLITUDE rabbit no (a) This C9C6E6%OOt
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0 ® I REPOW A o5oo/3o17.o9 RL21 (R) Blo z ~ REPORT A o5c ~ O 7 y CONCENTRATION l/1) DATA C (imio l 17 8 6 56 2 l 178 316 562 l 178 316 FfK7h1 TABLE STEP NUMBER . . o0 o 31. oo0 o o Q ACCORDING TC 0 TABLE A 0 - - - 5 25.9 24 19.7 3.2.1 e. 18 4 33 2 25 7 . - - - 3 2 2 cn . . . - - - 35.1 39.5 37.5 . . 3.2.3 ~ CD 1.7 33.4 29.3 - - - 3.2.4 0 19.0 58.8 42.5 - - - 3.2.5 c R - - - 9 39 1 3 28 2 2 3 6 A - - - . q. 31.1 37.5 . 38.3 . . 3.2 7 r c 2 0 4.1 9.7 - - - . 3.2,8 D Q 5 8 MEAN - 9.8 32.4 26.8 3o.8 35.2 3o.9 11 RSD (0/0) - 1o7.5 69.1 5o.4 12.3 2o.3 28.3 ~ 14 N - 4 4 4 4 4 4 7 17 2o 23 26 TABLE 4.2 29 CONPRACrION RELATIVE TO MAXIMCM NIOOTINE OOE7PRACTION (%), CR-1523 5, 29 MEAN TABLE 3.1o. AMPLITUDE ON rabbit no. 7 (a) This val vscscszooT
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h x s REFORf A o50o/3o17.o9 RL17 (R) B23 ~ N r COCCt2J'IRATION (ianol/i) DATA C fRCEt ' 3.16 62 5 10 0 17 8 31 6 56 2 too 178 316 562 looo 1780 316o TABLE c- . . . . . v o' 0 - - 40 4 2 59 87 6 - - - 3.3 1 co . ~ . . . . CA . . 72.1 76.o 76.7 3.3.2 ~ 15.2 38.2 28.8 83.5 74.2 66.4 - - 3.3.3 3.3.4 ~ m 0 3.3 2o.4 17.2 3.3.5 ~ 54.6 74.3 74.8 - - 3.3.6 ~ - 13.2 - - 89.6 66.9 - - 3.3.7 ~ c o.72 22.7 34.9 3.3.8 ~ 68.7 82.1 93.1 - - 3.3.9 1.3 14.4 39.5 3.3.1o ~ 78.3 9o.6 97.5 - 3.3.11 a ~ MF.AN 5.1 21.8 32.2 68.9 83.1 78.5 76.o 76.7 P5D (0/0) 132.6 45.9 29.7 17.8 9.0 17.2 - - N 4 5 5 5 6 6 1 1 TABLE 4.3 CONPRACTION RELATIVE TO MA.:IMCM NI00/fINE OONPRACTION (O/O)r (R-.1652 REPORT A o5 STEP NUMBER ACCORDING T( TABLE A 2 5 8 11 14 17 2o 23 26 29 5, 29 MEAr SscsESZOOi
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® 0 CONCF27FRATION (wao1/1) lo 17.8 31.6 56.2 1o0 178 316 562 looo 178o 316o DATA FROM "BLE - - -. 5o.5 49.8 39.6 - - - 3.4.1 4.7 11.8 13.3 - - -. - - - 3.4.2 2.o 2.5 to.6 - - - - - - 3.4.3 5.4 21.o 26.1 - - - - - - 3.4.4 - - - 34.3 34.3 31.9 - - - 3.4.5 0 8.1 19.5 - - - - - - 3.4.6 0.85 1.7 7.3 - - - - - - 3.4.7 - - - 17.3 18.7 26.1 - - - 3.4.8 - - - .44.8 53.5 56.3 - - - 3.4.9 MEAN - - 2.6 9.0 15.4 36.7 39.1 38.5 RSD (o/o) - - 91.4 87.3 48.8 39.7 40.8 34.1 N - - 5 5 5 4 4 4 TABLE 4.4 CONfRACTION RELATIVE TO MAXIMIPI NICDTINE CONTRACTION (%), CR-177oA 99E6ESZOOZ REPORT A o STEP NUMBEI ACCORDING ' TABLE A 2 5 8 11 14 17 2o 23 26 29 5, 29 MEF TABLE 3.ic AMPLITUDE C rabbit no. (a) This va
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6 0 0 k2EPOFtP A o5oo/3o17.09 RL17 (R) A5 CONCtNPRATIaN (imal/i) DATA FREx1 lo 17.8 31.6 56.2 loo 178 316 562 178o . 316o TABLE 107.1 97.1 90.1 - - - 3.5.1 1o4.5 104.5 92.9 - - - - - 3.5.2 61.1 74.7 78.3 - - - - - - 3.5.3 69.1 71.2 80.1 - - - 3.5.4 42.9 49.9 83.o - - - - - 3.5.5 8o.5 75.4 63.6 - - -. 3.5.6 76.5 71.1 89.1 - - - 3.5.7 40.7 73.8 71.8 - - - - - - 3.5.8 0 9.2 33.2 - - - - - - 3.5.9 3.2 25.5 55.9 - - - - - - 3.5.to 1.4 22.4 6o.5 - - - - - - 3.5.11 0 15.3 44.7 - - - - - 3.5.12 2o.4 61.1 90.1 - - - - -. - 3.5.13 1.2 19.0 45.2 - - - - - - 3.5.14 11.9 46.9 68.9 - - - - - 3.5.15 4.5 27.6 53.5 - - - - - -. 3.5.16 MEAN 5.3 28.4 58.4 75.7 81.5 83.3 78.7 8o.7 RSD (0/0) 136.5 6o.8 35.9 29.5 10.9 19.9 15.8 15.2 N 8 8 12 4 4 4 4 4 TABLE 4.5 CONPRACPION RELATIVE TO MA}(IMUM NIQOTINE OONPRACPION (o/©), CR-1772 49CGESZOOT O 5, 29 ME. TABLE 3.1 AMPLITUDE rabbit no. (a) This v. ®
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1002939368 v,LvO (i/TCAM) NOIMI119JNOJ 378vi o9lE oBLI YJCktd ll8 (21) lZ7N 6o'LIOE/OOSo V DiCklBN 4'9'£ - - £`9'E - - Z'9'£ l'9`£ - - V9l£t-31J '(0/0) NOIdL7VdS!^I00 3NIJDOIN WIWIXFtW OQL 3AI.LYT38 NOIS.OV2J.IN00 9'6 37eFLL E I £ l E I N (0/0) ~I 0 0 0 0 0 0 Ntl34! - 0 - 0 - 0 - 0 - 0 - 0 - - - 0 - 0 0 0 0C)Ol Z9S 9lE 8Ll 001 Z'9S 9'LE 8'Ll ol 0 0
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REPOKT A o5oo/3o17.o: RL17 (R) B19 ® CONCEN'f1tAT£ON (tanol/1) lo 17.8 31.6 56.2 lo0 MEAN - RSD (0/0) - N TABLE 4.7 CONPRACTION REIATIVE TO MAXItA.>hl NICDxINE ODNfRACfION ® z W O 5 78 16 62 oo0 78o 16o DATA F'IYkt TABLE N C cQ 5` 0 0 0 0 - - - 3.7.1 (0 0 0 0 - - - 3.7.2 ~'i 0 0 0 -- - - 3.7.3 <o 0 0 0 o. . 9' 3 3 3 =r ~ ~ cn 7; a :3 (o%), CR-1773 REPORT A c STEP NUMBI ACCORDING TABLE A 2 5 8 11 14 17 2o 23 26 29 5, 29 ME TABLE 3.1 AMPLITUDE rabbit no. (a) This v 69ESC6zooZ
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CONCENTRi+TION (Lnnol/1) Nm lo 17.8 31.6 56.2 1o0 178 - -- - 49.2 , ~•. . 9.1 34.3 48.0 _ - - - - 44.7 33.8 38.1 53.1 - 33.5 63.7 94.4 - - - - 82.7 1.4 28.2 76.3 - - - - 78.1 MFJ+N - - 19.5 41.1 67.95 63.7 RSD (0/0) - - 85.8 38.o 31.7 30.6 N - - 4 4 4 4 DATA FfmM 316 562 1000 1780 316o TABLE 73.6 79.8 - - 68.3 67.4 - - - - 86.4 87.9 - - 6o.3 80.4 72.2 78.9 15.4 lo.8 4 4 3.8.1 3.8.2 3.8.3 3.8.4 3.8.5 3.8.6 3.8.7 3.8.8 CONPRACPION RELATIVE T0 MAXIMUM NICOTINE CONfRACTION (o%), CR-.1274 m o4CsCszooi Y REPORT A STEP NUMI ACCORDINf TABLE A 2 5 8 11 14 17 2o 23 26 29 5, 29 V TABLE 3. AMPLITUDE rabbit no (a) This
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® REPORT A o500/3017.09 RL17 (R) B1 9 CONCEMKATION (ianol/1) '0 17.8 31.6 56.2 loo 178 316 562 1000 178o 43.7 84.2 llo.2 - 1.8 11.8 64.1 55.8 81.5 91.9 o.53 10.1 41.1 0 1.2 34.2 35.1 61.9 85.5 0 2.8 51.1 25.5 25.1 76.4 MEAN - - 0.58 6.5 47.7 4o.o 63.2 91.0 RSD (0/0) - - 145.8 81.1 27.2 32.2 43.1 15.7 N - - 4 4 4 4 4 4 TABLE 4.9 CttXJfRACTION RELATIVE TD MAXIMUM NIOrv'TNE OONTRACTION (o%), (It-1766A 14E6CsZoQZ
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0 REPOIa A u5oo/3o17.o9 RL21 (R) B12 I* CONCENIRhTION (unol/1) DATA FROlN lo 17.8 31.6 56.2 10o 178 316 562 1000 1780 316o TABLE 2.3 - 65.9 - 92.5 - 10o - 3.1o.1 - 1oo - 89.6 64.5 49.6 3.1o,2 - - - 1o5.5 96.2 ioo 71.4 3.1o.3 12.4 41.1 75.1 - - - 100 - 3.io.4 - - - - too -. 73.8 47.3 34.6 3.1o.5 - 19.6 62.3 80.1 - - 10o - 3..1o.6 - - - - - - loo 98.4 81.1 66.0 - 3.1o.7 - - - - - - 10o -. 83.8 6o.6 46.o 3.1o.8 - - - - 1'i2.9 lol.8 10o 92.1 3.1o..9 26.7 53.8 98.7 - - - 10o - 3.1o.lo REPORT A o
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0 REPOid' A o500/3017.09 RL21 (R) B13 CONCtNIRATION (ianol/1) DATA FFDM lo 17.8 31.6 56.2 loo 178 316 562 loao 178o 316o TABLE - - - - - 10o 92.7 84.3 3.1o.11 - - - 80.1 101.0 10o - - 3.1o.12 - 68.7 91.7 - - 100 - - 3.1o.13 - - - - - loo - - 91.3 76.9 3.io.14 - - - - 100 - 1o4.1 108.0 99.6 3.1o.15 - - - 82.7 111.1 too 118.3 - 3.10.16 2o.3 34.6 1o3.2 - - 100 -. - 3.1o.17 0.8 - - - 10o.2 - 100 - 121.9 3.io.18 - - 80.1 63.9 87.3 10o - - 3.1o.19 0 47.8 29.9 -. - - - 100 - - 3.1o.2o TABLE 4.io (continued) CONTRACTION RELATIVE TO MA3CIMLM NICOTINE CONrRACTION (%), REFERENCE SUBSTANCE REPORT A c STEP NUMBE ACCORDING TABLE A 2 5 8 11 14 17 2o 23 26 29 5, 29 ME! TABLE 3.1( AMPLITUDE ( rabbit no. (a) This va c4EScszooi
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49.1 MEAN 6.5 37.2 58.4 80.9 RSD (0/0) 134.5 42.8 45.7 22.3 N 9 lo 11 6 TABLE 4.1o (continued) ® 178 316 562 loao - loo - 92.3 - 94.5 loo - 92.9 - - 100 - - - - too loo.3 72.5 lol.4 101.9 100 - - - - 100 - - ioo 1o3.7 98.1 ioo - - ioo - - 71.4 96.o ioo - - 90.1 98.7 100 96.7 9o.4 18.3 7.1 - 14.7 15.7 9 8 - 7 11 CONI'RACTION RELATIVE TO MAXIMUM NICOTINE CONTRACTION (o%), REFERENCE SUBSTANCE REPORT A ( DATA y FEY]M 178o 316o TABLE C c= 0 STEP NUMBE T O ^ " 81.8 82.6 3.1o.21 - - 3 22 1o p' -o a:) ~- A TABLE A . . - - 3.1o.23 0 =r 81 24 3 - 3 1o m . . . ~ - - 3.io.25 0 - - 3.1o.26 CA 91.5 - 3.1o.27 0 =r  2 - - 3.1o.28 C 0 5 - - 3.io.29 "' m 8 - - 3.io.3o x H I i 14 76.9 64.9 D  17 24.5 38.8 2o 9 6 23 26 29 5, 29 ME TABLE 3.1 AMPLITUDE rabbit no. (a) This v, v4CsCszooT
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cN in~ao .-. •r C, O~re ~p'T . ~•-•--,y~ry:V'(V tf1 G7 L 4 q 10.0 17.8 31.6 56:2 100 178 562 ~ ~ CONCENI'RATIOfV (~um~olll r ~ F~T (; I~^~;r 11 .'.'"(V.TION/RESP0NSE CURVE, CR-1274 i r c__::.ale indicates mean vzlue) Mal
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Q ~ a S m ~ C I l~ ~~~ I 4] E. ... L N' a a ~ E" m 4' 1] . O r~ ~a s. 4. x ~0 I 9, N14 ~ 0 . f+~ 4 1'1 -; :10A 17.8 ': : 31.6 56.2 .. 100 `: .178 316. ; `' 562 , FIGURE 2 i x Z = n.~ Q Z 0 I Y K - ~ C0ftENtRATfON ~urnopll) ,; CONCENTRATION/RESPONSE CURVE, CR-1'523 (triar.qle indicates mean val'ue)
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x i' 0 0 hz 3.16 5.62 10,0 .:.t78 31.6 ,. 56.2. ° 100 178 '` CONCENTRATION Vumai/l'I CONCfiN'PF2A'DTOI9/RESpONSE CURVE, CR-1652 (triangle indicates mean value), ..
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,~. 0 R ~9 1 ~ ~ 0 1~. I I I I I I I~~. I I~ 1 10;Q 17.8 31.6 56.2 1& . 1Z8 " 316 562 F r CONCENfRATION (,,tuTnol/I) n!J'EtiTRATION/RESPONSE CURVE, CR-1766A ('triangle indicates mean value)
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r- I I ~ II II I oII ^ II y I 0~: p ~ E'i Z I ~ v ~ ~ 10.0 178 31.6 56.2 100. 198 316 562. CDNCENTRATION Wmolll) k , : <<f,PIi>tJ/RF.SP0~7SE CURVE, CR-177oA •._ irniicates mean vaIue},
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RvE;IFO lnstitut fh7r biologische Forschung • K61n REPORT A o5oo/3o17.o9 RL53 (R) B3 M H0292 GJ ',C1:0 1'7.8' 31.6 56.2 100 178 316 562 CONCENTRATION' V.unol/l) M 120-1 W '~ > IO QU 80-I J ~ F~:<>PO,7SF, CURVE, CR-1772 : ic.~*es mean value)
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~ U ~ INBtFO Ihstitutl0r bidogPsr~J.Ie forscfiur,4;-:, Klftm'. ° REPOtiT A oSoo/3o1?.~j9 RL53..(R)j 83 M r---r-~. H0328 r 10.0 318 , , 100 .:., .* 1000 3160 F.:' T (-,C„F 7 CONCENTRATION (,Aumol'/,l) ::rr^InN RESPONSE CURVE, L-NICOTINE BIS(HYLROGEN)-L-TAkTRATE r c i.,.M: e ina9 icates mean value ) - .~ ,_.....,.
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~ 0 ~ F2 o = .. ~ ~ iI ii iI I \ O IL » KMr 0 a INBIFO Institut~fur biologische Forschung • Kbin REPORT A o5oo/3o17.o9 RL53 (R) B6 PAGE 9-1 9 REFERENCES Bevan, J.A., Su, C., J. Pharmacol. Exp. Ther. 182 : 419 (1972) Chiou, C.Y., Trzeciakowski, J., Neuropharmacology 15 : 689 (1976) Endo, T., Starke, K., Bangerter, A., Taube, H:.D. Naunyn-Schmiede- berg's Arch. Pharmacol. 296 : 229 (1977) Furchgr%tt, R.F., Bhadrakom, S., J. Pharmacol. 1o8 : 129 (1933), Kirpekar, S.M., Garcia, A.G., Prat, J.C., J. Pharm. Exp. Ther. 213 :133 (198o) Levin, J.A. J. Pharmacol. Exp. Ther. 19o : 21o (1974), Nedergaard, O.A., Schrold, J. European J. Pharmacol. 42 : 315 (1977) Nedergaard, O.A., Husted, S., Schrolid, J. in: Vascular Neuro- effector Mechanisms, 198o, pp. 139-146 Smith, A.D., Winkler, H. in: Handbook of Experimental Pharma- cology Vol. 33, 1972, pp. 538-617 Starke, K., Weitzell, R., Naunyn-Schmiedeberg''s Arch. Pharmacol. 3o4 :: 237 (1978), Su, C., Bevan, J.A., J. Pharmacol. Exp. Ther. 175 : 533 (197a+ Suzuki, A., Funasaka, T., Matsumoto, H., Xobe Ji. Med. Sci. 19 : 111' (1973) END OF REPORT )IFWSI'

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