Tobacco Documents Online

. a SrytntH..ittnt un.1liNlrnl /4•ntx•r•lirra itt Ilrutl ruul.\'t•r•Ic flurttlu;;y NCTICE This T!?Val rrv ~e prote •!-l _ f c; g-t .;a). law 'T;tie 117 "~S ~ Carcinogenesis in the Upper Aerodigestive Tract/ ,. Charles W. Vaughan, ,tif.D.,• F'reddy Xuntburgrr,,til.D.,t Stanley M. Shapshay, M.D.,; Enriyuc Snto• ,tl.D..6 ancTl't7et• Rc'rlt fcld. Ph.D.i1 i ~ ~i.~4 : , <<' EXHIBIT NO:~ -57/a,iv1•'i 7 . l•hi, cli.culi.itm uf (arciltnl;cncti% is rnnccrncci nnl\• wilh the cle• \clopnlcnl of cImIcrlnuitt carcinnnw. \\'t mu.t lu•.t ret.nqniic that Iltcre arc t\%-n cep.-irate ancl distilict t\Ix's ol rlticlcrmcticl clrrinont:l tllclt ma\- cle\clop in this i-eginn: i lrl:uiniiin~ ttunnr (.~luant~ul. ccll cartnlunl.ll .uul •1 nnnlcl:ulniinl~ ttllnur (Ixxtrl\ cliflcrrtlli:urcl earcinttnla. I~lulllutelnlllrli~nn:c. ur lot Itlltinc le't lunutr). \(n.t lih\sic i.ut. t%*III rrailit\ recnl;nize the non• lcraliniiing ltlntur ac Iltt ont: IlccIuCn1I%• Cncuunlcrc•t1 ill tltu It.lur- phanlix. Hcmecer. Ihcre is a re;rclt:ll>lr lrnelcnr\• tct (urbet Ihac it n\:t\ arise at an\• pl:ce ill \\'alclr\er's ring, iuLIucliiig the I.1uci-1l ancl lin>;ual Inn.il. \Ltn\ rclx~ll. nf rancrl. iin, IIte tonal ancl Ixt.c uI Iltr Ituygur inlcrutix Ilu•x• autl x111auuoun tcll lunuon in Iltc aalis- tics. :Ilul ue cattsicler this ut I>'e i arriuns errttr. 'I•hex tuntun cliffer as Itl cclls of nrigin, itittlct};), Itiulnvic I><It:t.\iur. .Intl rc,lxtlt.c Itt nc:u- ntcllt. ' '.\.r.utt I'nd~.v~r~.ik~~+tvoent uf (A.bunnt;,ol.qgi. It4r.irnt l•nner.ul Sih4ul ill \le.li. I i1M;..iwauicChr•I.d (T...qt, l u.cr.n% Ilt.ni.rnt. \Li%uihu.rim •Ke.eunh I'nrlvwir ul R.rvswi l:iutctvt% laluuol 4o1 \Ldwtne. I)natnr. Rwr kt.ranh In.tinnt•. (:tiulwwlgr. \L~..whurn~ =A.avjni I't..l..vn. Ih-Itannlcni ul (h..L+nnt,,l..1,1. It.n+n~~ l'~u~tr.w~ btbi.d ul \led. uue. (autl. Iklu+rnnem uf nt..tjnug.J.Pz\. \•eterjns 1dminutration \IeAiol ( r~urr. H.wnn. \Ln.w huv t/. \i...- •w hnv tt.. /I)iit.in~ „I k~v.rnh. Iti..k~v~~.h IIWIIIIIC. tJ111I/1wlt(l'. \l.l,~„I~u.an~ h..u...l \•...tl, Iw....n -\•..t I•t \•. •1 \uq:,..l I'1,4U 111'(•q /r . ur CTR ~~~~ ~~~ ~ ~ ~"

1(!I (:11twl~a \1'. \'el1.n~• '11tC tclls uf, nt-i};irt of tllt• t•tlnuttnu (ct:uitliiitl};.•~Ilr.lln~lu. 11II ~ar~ cintuna ar•c tlct•ivctl I'romr thc n4lrtn:tl Inu1lltns n1cnllllallc lininy; Ihe, ulrlxr :tt•t•utli}Icait•c tt:ttt. '1'Itis tnc•tnlrtanc Il:t.:t };t•rntitrtl Iaacr: ltllit It is clc:trl.• selru•atctl I'rom the sullntuc•rnct by a well flcl111CfI I7JaCillritt tnctnhr;tne. l•hc ccllc m:ltttrc in thc cttnc nt:tnncr as tkin• crtt•Ilt tlt:u tltcrc is tul str.ttutn I;tanultlstntt. A nlajrlt• r 11:lr:tctcri.tic i. tllc Inca•ntc of a tttacula atlltcrctts. tlr itttracrilul:~r hritll{e. '1'ltis cpithcliunt tlt,cs not allrltw frtr frcc nti}n;uirnt i11' Icukocttcs tltrnngh it. 'I•he nrlnkcratiniiitll; tunlnr. I«wlrly tlillcrctuiatcd cart itlnnla. ur Iyntphtlcpithclit,ma has its rlrigirt tlccp itt thc tr.'llts tlf 1\'altlcaer'% ring at the intcrfacc nf thc mt•u•ltt Ilt•tllal an(l t•t ttwlt•rltt:tl TIIC t t•Il% art nflnltutttlrin, :lnrl IHwnlt tlilft•rt•nti.tuctl .llu1 It.ttt• Ictt fI1•.tluwllncs antl nn hascmcnt tncrnbtatlc. 'l'hi. clrulleliunl allot.s frcc lulgratiun nf lymphrlcs•tcs tln•nugh it, vl that tllc th:uattrri.lic hi.tolny;it Ilitturt• fif ctrcittrnltt:t :u•ising froln tltia tt•1) %.ill tIctnopnaucltc ur.ta .nul ivil•ul•11 cclls or untliffcrcntiutccl cllitllclial tt•Ils Ix•rlncatt•d t%itlt h1npIlowttt•c• \/ct:l•l:l•t•x to I}'ttlllll nowlt•a r.ill Ix• rt•cogniictl :1ft I>twlrl) dlllt•renu:ucd rartinnnta. I lie cllitltlni~llu,~r an~l t ltrli ln ttt•:unu•llt nf lllia tunl~~r .llr fli.. cuttecl fut•tltcr I1y I)r. 1):lnit;l \lillt•r irn lllt• .ltticle fttl Il.it;t Ilii. I•tlr• ther rcmarkt here :trc lIlnllnt•tl In tllt c:lrtin~l~ctlt'ais ,lnll n.uur:ll 11i.- tnn uf l.cr•ttini7ing cpiclcrnlnitl t:lrcinnllln. %%hiclt in tlle l'nitccl St.ltt•s and F.unlpc acatunts fclr over 9(1 Ircr tcnt ttf thc t;tnten ilt the Itc:ul anti neck :lrc:t. Fnr t111ulllctt•tlr•. %%r %\ill lirat lnctuinn t%%n rclali%cl% untiunnuln fnnns ol• l.cralilliiin` a<lu:lnlfous tcll c:trtintuna tlt:u as tt:t I1•ltc nn known ctiologic f:lctnrc, i.c.• nre nrlt rcl•nctl tn tohatnl. l. Sclu:tntnus tcll c:trnll•ntna of thc lloce and ainu.ca it Irt•llucnllt fnlincl in awxi:uinlt r%llh intcrtillg r:lllillnm:t or is rlivntt•rctl .llit•r vears of ti c:ltnlt•nt It or •'.illllatia.' 2. `'ct•rucrluc c:lrtinnnla I;cttcr.lllt tltctcloln after tlle tlllrtl fIt•t:1dc of life and most cntnmrmlt nccun on the httecal mucnus memhntte illtl nlt thc lruc \or:ll l11lrl.. Ita ~mltttll ia t•`ulllltttic antl •It:ulllt IIt•nlan.li- ccl Irrnn tllt ctnt•uuntlinl; lnurllcl .u1tl tltui is c:tal% trt:att•tl h% litnuccl Inctl excisinn t%itlt go,»I ezlx•ctatiluu llf cure. • Carcinogenesis ; The nt:ljorit\• nf lct:uiniiitt` wIlr,tnulua tell rarcirnuna. ~11 tltr '" upper aertldigruivc ttac't :uc thc re.nlt flf czlx/surr w todslttn. prlxltltcs a tcrit•s Uf chcln~ct h•atlillj,( tn r:ltl(cr: cnntcrat•I~• a r.lutcr ttt:lv al•ix• t%ltt•rt•tt•r a c:nctlu.~t n h.t. IKtn cllllllit•rl. Carcinogens A cartintt}ien is att :tgcttt that irtitiatca tltc (It•tt;lillntlcnt ilI tcnut•r. lllte cllctt i. ilimIt•lc. chow tl~l/trnltnt. lllc%cl•lllic. .nl1lllni•. .irnl Italtsluiaihh ul tltc tcll Ilros,t;tlt %%nltlu ItfIura. IIte cllt•tts ln.nlilc•t themselves only after months or te-in 11f clelnt•. Carcinut;ens lnmYn to ile eflcrtke in attiltlals itulutle mi(fi~t•nic' t•irtl%es. inniiint; racliati~ln. an~l lhcnlu.ll.. Itt nlan t•Ilirlclninltl`ic rti• tlcncc tug}(csts :t linl. Ix•tt.t•cn Iturlltt'a It mllhnnla attrl •tn ulv. t Itana• A carcinngctt apl,lictl tn tllc ntntllct i11' a suxt•Illihle intlititlual CTR HN 042-7-114-

91 f• 1.% 11// I•1•1•/M IM\t.•1 I I a tttittt•tl vinls (F:I>stein-13arr ••irus). 'I'he same virus mai' alsn he influenti:tl ill IIp- Ill•1t•I+/I/ItlClll +,1 IN,nl.t•latitlioing t'llitlt•t tn/litl t.1J1 itJUnla (%cc (r.lt;t: I(iK). It Irl. Iurtllcr Ix•t:u .u>;l;c•actl that wnuc Iltutrnt brcast c:lr- ciltuntas. w,/t/c leul:etui:l,. alul s:lrcnlnia may alsu be virtts intluced. Nutnt•rtlus thenlital antl ittlliiing carcinu};t:ns havc been shown to be activc ill the t,lll,t:r acn»lil;estire tract. Itlni/inl; r.uliatitm in the 1in-nt uf, t:llliutn h:ta hiauric:lih• Ix•tal ;nl itnl>,Irtaltt carcin/l/;en ill the tnuuth uf \\'ur{:crs who Irtinttat H;ltClt lI1aIS with I)JUIt CUtltaitllnb r1(It- tttn. •I'+/tla% illniialiull m:t% Ix inllllicatutt in tht latcr dercltllltuaait (1U tu 'a1 lc:ua u( In•im:n•% ttt:ullla.nu ill p:uicnts prt:vil,mlv ut::ttccl by r:lt(ialilln Iltcrallc +tr Inllrn.int" :lu c~1x/.urc tl/ tite :untttit; Ixlnth ill ).Il/.ln. Of tllt' ul.ult ln+it.n +Ilrntical c./rt'inu~rtl.. tlu/.c cunt;tinecl in Inh:lt/+/ nt• lllr uult uut•, Lllnl\It tu Ile u1 ntajur tlinital intllnlt.tnce iu tllt; 11(Illrr .It•I//tlit;c,tt\r 1t.ut rc•t;.)r<Ilcss ill ++Ilrtllrr tlle t/,ll;ltco is .nul Ic/L + Ilct+t•cI. /,r .In+,l,c1l .1>, / i4:lt s. / igart•Itcs. ill ilt Ilipcs. :\II lilrnt. ut ut'.+l.lt /.ll+ln+/`cl+it .Inll Ic,ll/ltr •1 1./14r t+,t.l) Il,,.t' tn 11.1\t: cll't't'I.'" Il+iI in1+,Inl.lli//11 i. Il.t,ctl url clli/lcnn/,1+,}lit c\it/t•n)c tlltlt Il.ls Ix•ctt .11+/11~1\ 1 t a.IC1I I» Illr lul.u / u in/lu.l r\ Inr ul,\ iutl~ ct+lnnntit I t•a,ult+. I Ili. iutlll.lt \ 11.1. Ilt•ru +1u11 l ill In,lnl +,ul tltt• alla ut r ill e\I,t•ttnlcrtt.lt t•\ nlrn+ 1• ill .u1,l,ut 1 lllt• +,I/\ I++u. , Iltu+.11 I.It t.. I I+,1\t \t t. llti% t•\ ulru+c iN nul\ .n.liLllJt. Iu 11 ' 1i:S t)+,ntcnt%ill' I,Ir,llult•It t.lrtinultta +/f Ihr Ln•l,tl>, ill alxlul IU IK•1 Irtu +If ulllliul,ll+l 1\It.111 it.nlt.lcr. r\Ir,.rtl u, ti);:urltr .nlul,tt I+,r Ixti+i+l. ++I titut•. t..tct lirtlllt:bl .u111 .L.+Mi.ttts' cll. tlu: liin- kt•v.ntl1 In•litutc oll+-t.Od tlt.u Iltt: t1lC uf J cJrtuu/5ett t,(lxcNtiblt nlllltll .tt.nu t+t tite !'.Inlt• •pt•tics t+/u1t1 clc\':Ite tltr Inttcletttc nt cip• Irttt; .Itu„l.t inclulc•cl Llltnt;t•.11 c:llltcr u, Ile.trl\ 21) Ixr ct•I1t u( tlte e\1/+1..•cl .111int.1h.. t\Ilrtt.l~ in .t IcIl.t.lnt ~Irain sinul:llr sllull.e cXllusure t.llt.r+l .Inll t.lnlcr. ilt ++Itl\ I llrr It•nt +11 tltc :ulilu.ll..tt \I+/tr tt•Irntl\ Iltlltltl+l t•t .11..= u.ing litttt.lt tt•Ivtt•utc liltcr ttltc. .In+l 1n„1c' ilucna\t• .Ir1c1 lnul+llly;t•11 c•\IxLUIC trW/ncns. Itr+r /lutt•tl Lu\tl;;t•.11 c.utlt:r itt nt:ulc atl Ixt• tunt ill Illt: .ulirrl.ll. uf tlte 1.ultc tal(in+,Srtt st/.ccptilllt; ittl)rtal ~Itailt. Tlte) .tla<1 ul»cu\rtl tlut a cclllll+,.c /lt•tttetl tnll.tteu .ul)I)It•nlcltt, C\trcl.• \tltt:lt ua•cl t% tlte b/,le itt"rcclicnl ul tl~arctlte Illu/llut.•tI .1 n/mtartine/t;cnit slnll{.e. \\'Itclt Itl• tni\t<I UI tulttct/l ri~~llctlrs itl tal~ln4 hmtxxci,ut.. ~lic s.Anlt Ilt.ltcrr.ll tc•tl.ttt•/I Ihc tartilt+,t;tnuit~ +11 tllc tt:a/111t1t; -.nlulr ilt a In.lnltcr Ntlr• Ixntiulr.l) tu thc E:lttcl (lltant in lllt: tig~ut:+tcs. .\ Ilux•rtr.lnlnse rc• l:Itilnt.11ip Ilett\tcn tht; alnlnl)tt /II• .tlulle I/lh:llctl :uul the iltl )tlente of L11 \ ny(tal t:lnt ur \.•a. .ll,u tlrnlululr:llctl bv tlilutitl}( titc inlt.tlctl lttulle ill tllt• ulimlly tllanllx•r ul tllc .ntullnt; 1u.1thinv. ultu.:lntl Ilcrnfcltl) :tre tli.- 111 tl)c Int+cllt :u'title \\c 11lnntl,nr4er. 1 rtllc tclatiuu,itill ill tllc 111.tlll/,git tlt.ltl`t:.lltlKltltt:ti II\ t:iprt:ue ,nlni.r ill .l•\ti.ln Il:ntl.tcl% t+l ll.t: It~iuna lnu\.n lu /Ktur ill tlut I.ul•ugt•s ni Ilu/n.ln ,Inulcr.. \\'t: It.t\t: .In.lhiclt tilc .tn.uutnit II>,atiulu ul tite tan- tl•luu. h,i+,n. +,Il.t•I%rll iu tltc Il.lln.tt:r t.ltNtlx .uui It.ttc tlt•Iitttt.l tun• Iln.iuu. .1. t„ tllc •i4ttili+.lnle nl Iltt•.t• /14:Itt•ttt• .Inult tn+tutc+i tc.wn. IUI 11•.IIi1.11,1J \' t.1J+ Iu++L+n{•.1~ tn ~l•nl•I.tl. 't . I..n... I d.-1.u..l..nn. 1 L.~+:.+++ \...:!i 1.n..luu. CTR ~~N 0~'2 ',`,~";~

•Ill/i ( :n trt I. 11•. \' tr$.n t. 0 t .tt • METHOD Iliattliigi(• a•rtinn.s ftnnt Ititllta~ %Ix•titnt•ns nl' tltr I:uttt., ul hunt:(us tt•Itu ttcrc Itcavy anulcrc tturr tttllcttccl :u tile I'atlulInw• Iu- stitutc ul• tile l•ttit•cr.ity uf liaa:I uItcrc tile cntul.ing hiatnics ttf It:t• ticnts Itavc I,<t•tt rccttrdctl attcc tile rntl ttf tile la.t ccntnt•t. •Iltc•t• sectinns ttcre cumlr.trctl t.itlt rarittus canti>Ir .liclrs t•cltrc.cttting, :tll stagcs ctf I:u•tttl;c;tl r:(rtin, Igcnciis ill tiyrtrctte sttutlc cxlw3,ccl. carcitt• ugcn succclttil>Ic Striau It.nnat•r..' It%tt Ituntlrcci •cri.tll% •cttiltnctl Itttntan Iar%n>;m Icntntctl f„t t:ctrcinttttta in tile c•ttllc(tiutt ni tltc 1)t•It:trtntcnt nl Utttrltinul;tt•tn>;- tll 1t;% ttf Yalc Uni%crat%titLitild nf Mt•tlit ittc. t%t•rc ttutlirtl itt clinlict,tu11n witlt l)r. J. A. I:itritnrr.' .tntl tltc IiK:uit1n. nl tlu• I.u%ttt;c:tl t.tnttt• nt tuctn trcrc tt1ntlsuctl t%itlt tltn.c lutnttl in 7'l ittta.ttc c:nutt• ~~I iltt lart(tx intlucctl itt h:tnntcr.ltt tig.ut:ttt: stnttl.t: inlt.tl:uinn. RESI:LTS I•Itc .ituil.trii% ilI tlti• t•Itultt•li.il Ic•i~~n. intlntctl tn ~.ttitn~~,tn •tt•. tlt.nt>;c. ~It•cr.ctl cclniltlc inltrt•cl lt:tttt.icr. It% ci;;.ncttt• •nmilt: tutl tile in biults)• .1)ctitncn. Itnttt Ititnt•in .ntnlt•t.' I.urtttgcti trt• •tt il,int;. SeCtitttts nl ctrt\ aa~t nt tile Itrnwtt•.•itc tr:ut.l~~rtn.timn li ~nt Itt)xrltl:t.ia. mctaltlacta. tl~.ltla.ta. .tntl tartinnnta in .ittt M iit\.I.nt• t:ntinuttt:t (IIta•r%ccl in It.ntt.icr% tmiltl IK• nt:utltctl 1)~ iniil:ir •cttiom. Irnttt huntan I)i~~l).~ ttt:ttcri:tl. 'lltc tt:o~ctnhl.uttc t%a• .utlt Iltai tnctc tuirrnxttl)ic .tutl% nftt•n tnultl nttt tli.tin>;ttidt Ittttn.ut ItIItn It.tnt.ict :\trntnt; tltr :'t111 .triallt .cttifint•tl Lutngc. Ill I:ittltnt•t'• (IlIlcttiliit tltcrc t%cre 3'2 gIqtttic atul )l ttan•::Ittnit It•tittns. nntl a'.t ttnnm. Iiit.ti- c(I in tile p)rtlmrttt anu..' Itt tltca in.r.tttte. tltc t:uttcrs tna\ It:nt- :uict:tt I~rrnrt .trafilit•tl vlti:ttnlluN cltitltt•Iiutn ul tltc•.t On tlit• ttthcr Itatttl. :141 .Itltrat,ltittu- :tntl .14 .ult~l~~ttic lc•u11tt. (ilt• fint••tltntl -11 tltt: itntinac Ltmn-4cal tunu,r.) ttctc lintittai tu atca that arc rntnnallt lintal I)% rratir:utm clrithcliutn. itttltutctl ht rit;atcttr •innlt• \II tile 72 i.na.i~t I:n~nt;ta) t.ttutr4 itt Itatttacm tKturrt•tl in tile :tntrritir I:tt%ngca) tt:t11 ancl in tile .u- ltra;;lnttir .trt•:t. IlI tile h.tnt.It:t I.u%n\ 11411111.111% (irtctl wtlt tt••• Nir:uur) cltitltclium. DISCUSSION OF EVIDENCE •I•hut, tile 'Nntirnntc (Itnitt nntcna:tl ItNltt•rltl:t.i.t ttt itt~.t•itc 1att• ( Cr) tt.c t ilx•tl in Itttnt.tn.. .tt in It.u t. titt i-:u cnc annlt• t.nt t It•.tt It In intlutctl in t•\Ir<•t intt•nt.tl .nnmi.il. Itt tttlt.tl.ititin #,I I i-4.ut itt• artttc..tntl ilumt• nl tile 13titi.lt Itlx• u•rtl tn uur ttcn It(mt liltcrttl ti% exlxrtntt:ntt. Itt c:trttnt'bcn --n.tcl)ttltlc It.tnt.tt•ra tltc tltatt~ct inclutccl in iltc C6TR 11N 042277"S

r I I • . ::.., .' : .; I (:•twl tx Ittt: l•t•rcw .\twlrull•c.rt.c. Tw.tcr Itl7 I:u-ynx by iult:llecl cig:trcttc attlr{,e rcltt•t:scttt a Iturclcl ttl• rvcnts itt- tltucctl ill ntau Itt sttu,l,t•. (lt:utgr. tlt:u tan tK't•ur• ill tltc t•catir:uur)• , t hitltcliuttt .tnc~tltrrt ill tltr Ilrt%cr rt•.Irircunr. tt•act. .uch as ill the brtrttrhi. 'I'his tn:tl,es the cigarette .mule itulucrcl Iart•ttgeal cattcer the uttly :ttailaltlc r/wtrnt ntlxlcl of brrntchttgrnic (Iuttg) cancer that t:rn Ix intlucctl b% t•t•ft:rt•nt'r (Itltt•r) (i}I:uc•ut•s tl•ith a a:tti.tit:tll)• .ignifiratu incitlcnce. In trsu usittg variuus xttttrkc tlilutitrns attcl ciwtrrnrs uhcrein lwr• titttls uf tnlt:tcrlr Itcttc Ix•cn rcljIattal ttitlt thr unntartinugrnic tuh:rtcu .tultl)Ictut•nt. (aIrcl. tttin, hilrn.at .Itutrs clc:u tllr.c•cll'cct rcl.•uiunships. I'his nctt :tttitttal tnutlcl Icnlh itxIf tl, lluantitcuivc cutttl>:nianu uf thr caninu~:niiitt ul ci~:ucnc .ntnlr Irlrttt tariuu~ t:lxa uf tig:trrttrs :lucl nt Ircr .tct uW rl.. I'rl,ntlrlin, Ialtttn ht•i}(lttcn titc c:ti•tittngenic rfl•cct. Knlttrn pt•tr rttntiug I:lt iirrs inl lullc t lictnit cll. .ut h ct>, }tllcnul (Ilrun(1 ill tuh:tccn .ntul,t•1. ti..uc• injury, :ntll gtlmtlr ,titrtttlant% .utlt :t. Itnrntlrtics.1° The Susceptible Individual "ctts witlt- \Ianv Ixlrltlc lrc cxlrlr.ccl tu tllliaicu antl utltcr t':u't'iturg lrut llr~cbrl,irtt :t c:ntct•r in tltt• ul'Ix•r •u•tluligt•.titr trcut lluriltg, tltcit• lill•titnl•. I.iitll• i. {.ll/mn .llwllu llrl• a•llul•nll• 1111111 Ilu iuiti.rtl~llt Irt .1 r.nlnul.~cn tlr tilt llcttllrltltrllu rl tllc l.ltucr c~ltlrt Ilrr alntc gt:ncrai ulr.cl ~.uinrn: ('•ttcinirt,enesis takes time. Carcarcittnl;ens (Irrnml>tin>; factetrs) .It4,,tt•n tllc l\:Iiting little. I I,r.t I•u tlrrx. au It n. l;cnctit itlltt•titante :tntl Ituntoral •utcl lcllul:tr itnntnnit\. I,I•ty att ulr\iuus bttt :(1. \t•t lwurll tin. IICt\IIMMI r"lc.•" 11C lnnw 111.11 AItlIItlrl ll.ccl tlr vrtt•.s i:l, :tltttn.t •t It.lntl- nr.ulic•tt ur l~~lr:Klu ill tltc llt~cl~ lrnlrnt nl cantcr ill tlti. It i. nut .1 l.nlinll•~tn Illu Itrlrlr.llrl~ .ilt. .t. .t tlK:trrtnl~ttn ill an ,t. \rt tnt• lrtu~~tl I.l.ln~nr•' lintr ti..ur injlm anll .tlululi Ill• ~tu~~tlt :nr tlK•lll in- u~rtt., anttltitt~ tlrtt atis a.:t lltrnnit Lw:tl iiritant (tltt: Ilx:tl irritatilltt ill .rltululL 1>'Mrt' tlcntitinu :uul urai htgicnv. ,\Itlltlitit I'luntat ill tli prutuutc tlit: tlt:\clultrncnt ill tantt:r. Fht: llc.truttkt: ONYt ul A- tirltul ill iltt• Ii\cr \er\ lil,t•It Itl:t\% r rulr. fltcrc it, llcntsrnstralrlr li%*cr llt•tan4t?nunt ill 5O lx:r trttu lrI tltt: llutit:nas t%ith ural t:u.tinutn:t (tuult ta.il% lrlt.ervutl itt tile clcv:uilrtt ill Ihc :tlkalittr Itltn.ltlt:u:tar Ic\cl). I'lti. ttt:tV ill turn tllt.rl tltc Illrrtunrtal Ictlanct• ul' tltc inlli%illttal lrr titc aatu. uf tltr It.ttit•rnt'. rtattual inunttutitl 1wc It.tgt: •Ia:(l. "Iltrrt: nt:,). a1w Ix I/"l ti,.uc lartltt-N. Itilwrllatitt tlclicicttq Ic:uls tlt tttut•naal au't>,- pIty :tutl It%lx•rlct:uu.is th:u nt:tlc% tulrtu.c .lin nutrt: btt.ct•lttiltlc tu t-:u•cittugcnit' a;;cuts. 12clxtir ~•ni~tnc. nr•ty Ix }(cucticalll• clcliticnt or ' tttav Ix inllurnctal bw utltt:r Gtcturs. sutlt as tlirt ttr litt:t• tlix:tx. N~lua- tnuu. (cIl l arl innut.t is nnt Lt.•nrtit •t1k intlxrty:utt ill tlu: tt.ual .t'ttst: lrl' tltr t.ntll. Ilnt~c:tr. attt >;rnc• tltat .trc uua•tlric tnct) I>< c%lx•ttt:ll tlr untlcrgu nrut:ltiun tturrt: t::t.il\ :tutYct•tcutu•tll~ lltrtclult c:u-tittunta. •I Ite Itigh inl illrnct: nl• Ithar,tnt;c:tl cart irtnnta ill tlte I'lutuntcr•\•inNd nt -.\•tt- litlrntt nr•rt IK .ln c~•nnlrlt• in llt:u tltt• Ilrn~ trttu itlrn •uul rilrlllatin lll•lu il•ni rl•. •r../x i:ut•ll %.ttlt tlri% llia •iv •ul• 1111111 ln4mn til .lllil t ntt- tl. lrlrrnlt ia. t..,. TR HI 1 0402". 77t

a (:n%wtt. \\', \'Arl.u.t% lt •tt. Muco.al Changc. On t•N:Intiuint, tht• ntnctt.a Itl• :1 Ir.Uit•nt ~tlut .ntnl.cs, t~nt n~~ti~t i };rcal tau:uittns ill its altlxarancc. Innn c••cnliatlt tutrntal cltitltclitun tltrttuglt a variety tt(• '- .Ilanttnalnry :Intl tlt.ltluaic clutti};cc. Ixtssilth in- clutlilig 1•r:utk cartinuttt:t. •I•ht: rNtrnt ill tltcsc th:ut`t:x altlx:us tu Ix•:u• ~ a direct rclatittnatip lu Iltc wtal tht.c ttl' c:urcinugt:tt a)>Islital. In Intli:t whcrc tltc Ixctlcnut (a ntixture nt' u,hacctt :uul beetlctiut txr•clsitutallt• tnixc(l with limc) is held in Ihc rhrck Ixtuch• thc cattccr tlctcln)n ill the buccal muct>.at. In utuntrit:c t.hcrc tnh;tcctt is burttr<I ttithitt tltc ninuth, tttic mi} ht cxlxct ut lincl Ihc Ituntttt• :Itljctccttt tn tltc hut Il:unc• but ill };cnt:ral lunttn•s :u•c fnuncl in :ncas sit I„Ntlin~ ttl• t)tu xtlita tthcrc tltc carcitutgrtt ttutt• rcnt:tin itt tomt:ut t%ith the mucttca ntcr Iung )xritxlt nf titnc. '1•hcsc art• :tlu, thc u.u:tl arcas litr r:ttucr ttt tlrtcluh in patit•nts t.lut sttutl.t: ci`:trcltt•c. Itiltcs, ttr ripr• in tlte tt.u.tl fashion. Thus tte lind the majt,r n,ucasal changes alc,nt; the Ih>.ir ul, thc ttt()tnh. citlcs :n:tl hctcc nI Ihc Irntgtlt: untl rctrumttl:n• arca. :Ind :tinng tltc Ir,tl:uirtc ntlt Itut r:nt:lc stu tllt• Iwtt:tl mttctrct. '1 )It• Iltu•ann ul' tltt: Ittngut: i. a1lnn.1 nt•o,ct• intttht•tl. 11 tlu• •tltplualutn i. uillt•• sprca(I as it must Ix' in thr t•a.c uf a smtilcr, thc changes t%ill I,c ttitlc• spread. ~ \li~rttaul>ic c~atuin.tti~ttt Ix.ns nttt nur tlinical itnltrc••uitt Itl •'ftci<I catucriiatiuti•'• 13ittltct .hcfirncns t:tlcn Iruttt tticlch (lilit•rcnt areas shut% t•aniny tlc,,rccs ttl cltithcli:tl :Itt)tism. . ~ ('.tst I. A lill tcar nlll Ittnlc It:ul .nuAt•tl nnc In tt•t, p•ult nf tq:ut•ncs hrr cl:n Gor all \cara .nul h.td usctl .tltnhnl ill c\tt•.%• Tht• oIctiuu-at %.a. Ir.ui thc Htntrnt it•at %%:t. Itcg:tu.c• •trnJ a li%t•r crtittnc pniltlc th.mcfl nulcl 4Ic- r:tncetncnl. '1 ht•rc %..t% irtu,wnn :tntl •utoiltlt% ill thc nral utmut,t ,nttl a rae- Vvi1. al~l~.u~ntlt .ulw•tli~ial 1tl1t•t.itinn .,1 4.1 t'din• 4111141 ini1na ..1 tlir tultcr,uiun oiI tlit• vilt ltal•ttc •tnll ill It.n .ut•a. nl tltt II1Mrn nI tltc ni'nult• (1u11*• s) slx•titttuttt t:tlcn Innn c•ttlt arc:1 •lumctl tltt• GiII.mntg: 1.'1•hc an(t Ir•ilatc tlcrntinar•uc• cltiflt•rnMsitt c:utiniinta tFiL: I1. I lictc •ut• tulx•Itnltcli.tl gwitlt. ~if ..In.innml ic11% iInpl.mnt; a m,nlccl t:nmm.w ill iir :tutt .It:yx•. 'Wnnt• IlI tlte trllk tomt.titt lt•t:tritt: ntulititutlc:ut~l trll. .uc stOttalsl• x•cn and all t•Itithcli:tl pcal i. Irt4lutitt.•nt. 1'Ltcuta tcll. .tn4l I~~nl~lu~ t%tes --urmutut thc nt•%III.t.IK Inltltr,nc. Ihc clntltclium tltrn.o; mmlt•t1 dwir• g-.tnii:uinn fir tltc haa,tl tt•11 la.cr %%ith Iir.m ul thc Itnnn•tl matnruuntt•tl salucntc nf Ihc vlnamisus tt•Ils• I hc•rc i% pn-mtncm ttutlc.tr .utln.t. 2. ')ltc amcnitr Ilortr n( Ihc 1114111111 shlm. tarttrntm:t m.ntt (Fi`. There is tatal tlisnruanintiun nr the Ita,6d tell later. althowoh the Icttcmcnt mcmbr.ntc :tplx•:In int:tcl. 1'ltc nnrnt.tl attlmt.ttnt• ill tFtc wIn•nn,rua cltnht:li- tnn is nwtlt•tlh• iliuoint•iI Ihroint;luout thr lull Ihitlne.. ~it tltr t•Intltcliiun. In• tlit idual t t•II. ahnt% lth ~nnurltlti.nt .nul 4m% ul .1 li•u Acll. 4\t(sltl.t.utit lct:ttitt. I ht•rt• i% u tt•t:tulntitt ill nttAh•ar .iit• .Intl .It•t1K• :uul ILt- wlhhtlut. '1'ht .ul.)tithtli,tl i'lnncttttc •hrn. :t Ot•n.c rnliltr-ut• ill htn- Ithirttt•% :rrt4l Itl.t.tn.t tt•Ila. IFhc It,ta•tnt•et Int•tnltt:utc i% int.at. :1. 'I ht• I:ucr:tl Ihror ill tltt• nuiittlt .Init.. tlt•Itl•ni,t (fi` a). l lu Iatcr is itu:ttt. fltc tt•II. •msl rnutki atc ~rnctalh uttilnrm ill .vr .1nil .I1.tlx•. but simir pIrimtm(tlu.ttt is nmtctl .nnl nut h•.ttctl tt•11. e\tcutl iIomc tn tht: .nr- (ace. •Iltt• .trthitt•tture nl tltc eltitlttlunu ia vt•nt•rallt ltresent•tl. .tlthuotuFlt it i% tlurlcr Ih,tn mirnt,tl, CTR MN ~~~ ~ ~~`'?e

. I . L~ • ` a ~ ~wr• : ~'J • • ~: f•.: lj. •!.* ~ - arl:a arc < ~ tn/lre rutnnllln Iltan ~cnrt.lll\ rclIrtcll. .\ rclcnl .lu(1\ Illulc :u 11tc li/hlun ~'ctcratts :~/Ilniniatratilln ~Ictli~al C;cltlrr Inne.crnctl 1:1/1 cl>n- x'tuli\e 1/•ItiCnt. \.itlt .1 cli.l~nu~il ul Ilc•ul .11u1 nctl ru~inllltt.l Jncl in- ~lucl~tl ': I ll.llicnu \,illt 1\%u 1~1 inl•u ics. 11\c II•Itirnt. \%llh Illl l c In Int.ll'IC~. •In/l t\%n It.lllrltl~ \%illt Ii\c Illun.llia,•. 11'.1141uircl Iltutln~ the nu11.11 clt• 1f ~ .IT~'t. :! . ~ ~ y . ~ I11•111/' . I .II.IIL.IL.I II/ .MI/.•1 ••111.• ••/ \\IV111•NI\ 111M1. /I (..\Nla\IN:1\1.\I~ IN 111/. 111•1•/.N I N.\/fl' 4 q J " ~.~~ r ~ ~ `~ `' '~` . ~ : :~ - : .F. . ' t ...- 4 - ~' ~ ~ i r~ ~` ~ ^ •' • r r_ •~ ~.. i ' • i I \ 'r ~- s ~ ~ 3 Ji • 7 ~ S ~! K~ ~ ~ a i-" _ ' % ~ f ~ U! ~Y ~ ;.~ ±'r~L; ~ ~ ~~ a'lj ; ''•L. ••.. ~ •.,.~. i ~ ~ , ~ t>r , II 1 ' I . ~ ~ ~~ ; `4-' ~ ~ t . , t~~''~ ;~V r ,, ~ , .1• ~ 9 • t~s~ " . G j 1 ~s.~•~!rro*:.r't Fl,lnl• 1. ~.IILInY111./111/.ft1 uNNq.lul ./11 II.IL/1r. • 1 •r .. ^t~ ' ...:• ? W-i a ^ •v -+ .'~~~ I • ~ ' ••~ . ~ • o+ `y a f~,. "• . - • Ai a;. `ti•1•:y ~ •. S \ .. V i..~'.• .. V , ~ • • .. .• • .\~. : i ~. ~ •.' ~ ..~ t J r 1: 1 :.~ •ie• . ~ •{ ~ . .~ f •~ `.• ` 1•• ` . . ~ ,tl ~~`~11+I. f • : a . V•.~•+ Z •liccc tlt:u 1u1111ip1r .\lulnunwl. Iluuun in tlli, I> 1~' ~~~"~ ~~ ~~~r""~9

/1 . ' Illl ~,~_~.. l:n.tkt t. \\'. \'tt I.itt• /1 u. ~.. . . ~ . . .•~....t..=r ~ •~ • t` '• •. i' ~ :: XN'~ ~0. ~ i!; ,. . og, lJrh. .,W ~ . .~~ ~~ , : ~ , ''.,,i • ~yr,~; .~ 1 : . ,,_~~},.. ~~~ I~• V.T .I: `~- . ~ '~ . ` r_I~~1 :.•1 ^ '9 - '~, _y a . , •• A! .dI Tl ~ I ,•. , ~~: ; • ~ • • * • ~ •_S ~ • A. l ~ti ' •. .!~ 'T 4% t •- ohr... ., t! a < S I~ ~: ~ ' ~ i i . ` . .. %I ~ . .Y r ' .. ~ ~.I. 'v`'•)%~":~• .~ 't:, ']f~ 1\.• rCJ b-4 / •.~' 4p:1 Fiy ~~r0 '1.' ST.I~Li...t Ileulnl~lal~.~l •d IL~i .d mnutl~• priln:u•y.:I.cttlntl Ilrinlalc nt:tt tlt•ct-llll/:ll :ut\ linte. tlnccttltic•c. In Ihic gri,Sllt of Irtlicnla nitlc tll Iltc caccs „I .cttcltrtttn,us tulnctrs intnltt:tl <•:tnt(•rs nl Illc c~tl/ll.ll;ttc. I he.c t It:nt.,t•. :IIw1 fw t ttr nn .1 tt•ntlr1r:tl It.t.i.. \\•c rtv alI 11t:t1 tltt• :trlinn nl a cartirn,~t11 rt.ltlirt+ linlc. In Illc atrntli~c.li~t Il:ul tltt u.u:ll rttlc `tI tlttttttll i, tlmilctl t. ttttc Ilnt l Ix•r cla\ Inr 211 \r:tr• (.t1• 111rntgII in :I( tu:ll ltt:u tirt: 11 i. Ittnrc nllt•11 11) ct:rr.l. II 4tnc I41II41t.. Iary(t ntttnlK•r% ilI atw t I~lil~lt lt.uit nl. a Itl) tlt t~Iw~a tl In t:ut trn~~rn. mt:r a l4ttls; lx•litwl ttl lirclc. il i. ttunntttn 1„ nll.t•rcc Itt~~Ltr••itc t1tuattt• trnclttl>r•ntc altlli.ln Irntlt ttl irril:tlittn, Itl It:nt,npl,ll.i:l. Ill c:uCinnnl:l in citU. Itt it1v:(Sivc c:n•ciltttttl:l. - (:.t.r. .i1S tt:u gJd nt.ilt• %%Iwt t%a. tI.nln1t•i1 Ill .t mtnt.1l in.utnrt+1n ctmilrtl ttwmt: Ill.tn ttm Itatl. n(tit;art•ttt% Ix•r t1at. Ill I!Nili t.lulc ~tmlrr~ int; , tlrtttal cmn:uti4rns Itc t%aa u,1tt-d tn Itatc t altht• Ic.4m. culxlimlr~•.tl iin y;t•n. ~ crat mucn,tl irritatiint. nn tltt IL.ir si( tlhc It•It .ifle Ill iht• itu'mlt. ISn~ln. _ chrn.t•tl m:trlt•tl alclti.tw :Ind Irt••~l/lt• t.u(ntnttt.t itt •ilu. Iltia t..t. Itr.uttl It. _. Ioral Iulylur:uinrn :tntl Ihtvt t:ncl1tllt I41Iln..t•tl aith tt•Ir•.ucil t,1lnulnic I1lur •n. In:ttil.tl .tainin4. In .\Itril I!Mii Ihis rt•aalcal .t .uIK•Ilhti.tl t:n4nt.nn.t ilI thc It•Il utitlllirir ttl lltt• nwouth. tthwh t.a% ttt•att•i) Iht t•L.Irirn.t`ul.tunn. .\n4dhcr .ulxrlitial t:utinuln:l nl tltc .nut•twa Iio.,r gei tltt• nwnuh ~.aa lulttuatt.l iu St•lacutlx•r 1!Ni7. lit I!Ni!( .1 .ulw•tltti:tl t.umntuma nf Iht• It•II .tntrti,it loill.tr ntxl tt)n.ill:n• Iina .g:n uc.1tt.I In I1r.1l t•\tt.u1tt .tntl Icll ratlitaI nt.t ili.wt• Iiun. In j:Inuan 1!1711 ;uS arri ni k•ulnlll,tlt•t oiI tltt riqlu antt:tiiir .t.lx-tl ilI lltc Il(rir Ill lltc mnuth rctnutctl 11% cve•iom.tl hinp.c. (:artim.tna nf Ihc I)a.c ttf Ihc Innguc t.aa tliv4ttcrctl in lulc I!17,11 :tntl Irc.ut.l ht tcdt,dh•till ra- tliutltrtaltv. Ihc It.tuctu ctcntu.tllt .utttttnlrtl Ill Itia tliva.a. Itatitt` 4lintutl• .n:uccl mullc .i.\ .cpar:ttr 'primancs- u.cr t 1x•ritrl nl Itiur 1rat.. If tlu• :ulittn nf :S rart•iltttlncl 1•ttilttirr• lilllc. a•c IIStI.I rrlncntlxr Ill:u itt :1 .u.tt•Itliltlt• intlicitln:tl. t•ct•n 111,11101 ••cutt•tl' ilI Iti. tttigilctl ® CTR HN 042."~>~`~#~

a . ~ 0 ( twta~tK.t:~t_a~ tx tttt. l'rrt.w .ttwnnu:t,tt~t. I•w.u:r (:.ta t. A 3t1 ttar nltl Ii•utalc %.a% lita trr:ut•cl in I!17a T4cr .~I~tamnus --crll carn-inuma nl the ri};ht but•t:tl mtucwt :uul thc k•fi rctrmmil.u• tri.gnnc. 1hc n:n t:ut•Iull% Iullnactl mcr tlic t•n,tiinK litc ~car% %.ilh nu c%idcutc ul• rt•cur- . rcntc ill tltt, urigin.tl tli.cax. tltrrt•bt (ttctliltinl; hcr Inr a"litc )car turv." In 19.80 NAluarn4ius tclI c-:u•t•innnta %.as clixut.rcct ill thc ril;ht rcn~nn~d.tr tri~icnc. CONCLUSION We ,ec th:tt a carcittngctt (tnh:tccu) appliccl to the ntucaus mem- br.tttc nl' thc :tcrtxligestit•c tr:ct 40, a suaclttihlc ituli,itlual (hc:n•1• :tl- cc1Itul intal.t•• IHMtr tlict• Ixwn• ural k-icnc) nt:t). pnNlucu :t ,crics ut' cltan~ts (:tttl>ia, tl%skrt:uu.i,, t:n-tinunt.t in situl. tlltitlt 111.1% Iead ttt taninl1nt:t. 'Iltc .autc Itltcnmntett:t lKCtu• itt ..uit.thlc itthrccl titri•tn It.tnt• trrs inlt.tling ci-1-irettr Sint c tltr t•:n•t•intrgrn in IMItlt tltcx in• ,t.tncr• i, t~iilc•Il :tltlilit•tl. tltr t•Ilt•tt, %.ill dr%t•If ill utt•r .1 at,Ic arra Itctntt•i1 "Itt•I/l ( .tutctlit 11.1u.0ttt•i "). 1Vc %.ut1ltl cxlmtt..tud ill Lttt IincL 111.11 ntttltipIt: ttuttcw% are tutntnutt, but we tnua tcm,l, lur tltt:ttt. lincc tltc tlt.tn`c, Itttxlutccl It. c:utinu%zt•n..trt;.ulclititcantl irrc.cr.ible .tutl Ialr •t Imt-, tiutt tu cIt•ct•I41It. t%t• t%Ilttltl t•~Ixct..tntl (lc1 ItttcL 111.11 .tti•. 41ntl. tltitd. .tnd 11)ut I It lit itu.it it•..nc c"nttuntt.'' tiinc t• .tll tnuc nu, nictn- hr:utc c~lt~„tcl tu tltc t:uttnI)grn is tli.c:t,ccl .ttt(I sinct: it i, itnl)(,..iltlc to rctuMc ur /1t1tct\\isc trc:u tll ill 11113. cli,casrcl tuutmus ttu•ntlti:utc. tltcte i., nlt ,u1It tl1itt}; a, .1 "cttrc." Itutlt." : fctlluttittK trrattttcnt, unlt Gtc (6 Ixr tcnt) clcvclctlxcl t lunlter canter ill r tuh:rcot t:titical :trca. 'I Itis ,tutl)• itttplity tlcu tuh:tccu. lxiny the uttlv ktutc.•n vari:tble. was a caus.uite agrnt ill catucr clevclnptiient. f.tlually imltctrtant, it imltliccl tltat if tlle exlxtan•e tn thc carcitt,ben j tras staplxel. thu iitciclt•nte ul• Iutthct• tumttr development W:ts ttu I higher tltan tltat in the nurmal pc,luiLuiun. It seents tthviutu that fur- i thur snutLirnyl ,Iwulcl Ix iturnlittt•cl itt :uty Is:uictu t%lhu has prt>,ccl ~e surt•t•lttiltic lu 1114: tlrvclitptnctu ill a r.tnccr ill tlti. rt•4itiu. ltt I!NiK (:astit;liattu,' ill :c rt:t•it•tv ttl• KS) Itaticttts x•t:n over a fctur ~~ tuctttth IxritxI, (nurluclccl that cc.atinn ctl• ,tnt1l.inl; h:ul lit) ittllttcttce ( un tltr clctclulttttcnt uf a,mUntI Ittinr.trY. Iluttc,cr. Itis ntctluKl uI• ~' Is;uicttt ~clta'tittn tras suclt that tite rc.ults .nul t;untltuiuns are tt(' tm- knttwtt t:tlttc. IStv:tusc ttl, tltia. in c1i.4u.,itt4 1ti., rcl>,trt (:.t,tigliann ,t:ut•, tlt:u "1)t••Ititr tltc :tltlr.ttt•nt inlt•tcttct: ill 1x clracttt I'rnnt ,urlate _ anal),i,. •trn~liul; i, It.untlstl tu p.ittcm, iittciI ill camc•t ill tltc t,1h•utu 4i iliral trgii'tt. / lnl• iuu.t L,ll. I. lurnl ilu .t.ut.til. mil .+•.mst Im tltr Iipta1 ut '.1):1 p.uicnts. Hc rclHlnt•tI th:u a sccutul t•:tnccr clevclulxcl ill a tult;trc•u tTitit:tl :tre•a ill aS) (au Ixt ccnt) ul 122 Iruirttts ttltu tuntinucJ Iu stiiul,e altcr heittg trc:uecl. OI the 8 1 lr.uicnts t% ltu ateippe(I sntul.itig EPILOGUE In I!Ni:1 1>nltli,ltccl Iti, t.cll knuwn ,utvcy ul I11 1>a- ticnu c.Im It.ttl Ixcn trc:uccl ,uttcsstttll\ hcr t•antcr ill tltc uplxr .tetu- <lil;c,ti~c tr.tu. Iti 1971 he puhliatrtl :ut e\ten,ititi uf this tttul,• ul a l..r• Tf`se f f f''f 0'"'f' 2f' C~ .1t.

a I •)1 4 1:n Iw{ lo. 11'. \' Irt.,, t. t { {t. II In{,.I 1K• rt{n/InIKn,I IIc11 Inlcxlt, ttlnl:line, IrlIl{ i{,ili:,ltn. (II1l• hyclrr,carlx,l,s) anll Ilrt,lnult•r. (I,Ilrlu,l.) :{nrl is c••c{lli:,lly :1 {tt•:Ik /:,i'. t•i1Nr};cn rerluirjn}; :I Inl{y; cxlx,.ui•t• Ili rl•al II a Inl:il t•IIt•( livt tltr.c. "Illi• snlallrr Illc dose. thc Ir,ngrr Ihc rl,luircll cxlxrsurc (Illc t'„IIvc•m''it; alW) truc). H:Ihl,ih•• cl:uislir% havc shnwn th:u 11{c jnciclcnl'c r,l' t':u,rc•r anu,n}; hcavy snu,kcrs who sll>I,Ixcl .nurkilly; has clrnpl,ccl Iilrlhcr. Ih:ln h:ul Ix:en exl,cclecl. (:Iillirally tce do see :1 rcvcr.al r,f irritalitm :ux( Icuk/,plal:ia {t hcn inu,kill}; ii mu,hllrcl. •1'his implies lluu whc•n 1r,/h faclt>n ul' illilialiun clncl pirr,lnt,titm :{rc r/•mncccl. thc irl•cccr.ihlc clli•c•ta nf Ihc 1>:ISI inilialirm may rcllr{ill uncxprccsccl li/r the rest l,r the p:uicnl's lifclinlc. Evcn•r,ne Inua Ix I:Inghl Ir, avoid :111 li,17m „f Inl,;{ccr,. Kt•n{cn{• bcr alx, Ih:ll clfcclj%c Icacllil{}( jntluclc< Ix,lll Ilrcccpt :uul cxvnl,lc. REFERENCES i I 1 1, Ik•rn/oIJ. 1'.. IInn1L•tvt•r. 1'.../rol Nu..Ilt ltl. .\. II.:•1r,:Nn Ilillt•IrINt In lht• Ir.lulv• Ir) itltllPrl \tliall h.111t.11•n trt rlg-.ntytt• N1M.LP I/IILILIINNI. I. ~.1/. (.nNrt Ina., 17:1111 -1137. I!1i1. • 2. &•rnlt•Irs. I', IInnJ.•rqrr. 1.. v.tu. I•.. IrNI I'.u. 1:. I.: (:Il;.nr•rlr .rnl..lc nlh.ll,lrl.m .uuttit•s in inllntl 1tr1i11 I;.d.lrn Il.mwrl.. I\,u. (.uNt•t In.1../11.1r7:.-+ri-,, 1979 3. (aul9lelntt. `. (:.: InllurtNt• nt InntmlN-el .m/.lmg tm tht• i1NNlonlr 4.1 v.r.tNl Ini- nlLtn.:Iltlrn in.r.ltilll( ILNl/ll, I/Ilar\/lt •IINI Llr\Ill,,. .\111. Ilt•/11. .\NIt., :IvS. 1lwiM. 4. I1tNltrlr..dl, 1\'.. ( hrt,tlit•t, II. 1.. .lut1 Il.lrlo. II. I'.: Into.+i~.llua...m 1bt• t•Iloll..,l Illmnr til;:vcut• .nN.lr inh,lllurlu Ili \tnan `.drlt•n hamarn. I. \,n. (.uNtl• Ina,,,J1:1iN1-I`t'f:, I!175. 3. II. V.: (.111111..u1•Il\, t•1//tI1N• I/NIII/IN111 .IIw1 ll•Il(• :NINN1. .\IIt. (.II11t•r 1(rt., /q:l -KI. I!M1T. fi. llnnd.•rl;or, F.: I,nlnt' •nNl I.nrin.rul,t nl tht• Llnm in 1tn,lu h:tnt.+vl, t•tlr.KVl trr.it!ett•Ilr .nN.lr. I.Inn{n.....IN•. •Yt• I`t: 1-1•rVl. I!1::.. r 7. IL.ndourgt•r, F.. `w.r, I1., \ItlNdl. J., II,IlIIN•n, 1'. .uNl Ilt•iv. I'.: \nun.ll Iu•.lrl .d hlltn•an rliv•a•l•' f:1lI1n.N11:1 4.1 tltc Llltnt In Il.nn.tclt ctlNntYl 1.. tl;,.ut•tlr .rn..lr. .\In. J. I':1111., xI,'r•-V IM. I!li!1, N. 1u•Ikr, .i. %.: (.Irrh.mlt .d IIN litcr. :Ilt.dudian :nwl htatt tmnlnll; ,LV.i.ut•tI r.ith t:nNrr rll 1IIC m..uth .nNl lill.lrtnt. /Alrt r.:(/: stll:.-I11:.'. I!Mi~. !1. ILinhtNt. I. .\.: 1„n hmwlrttl Llnn~K•.J I.nrt•r.: lutlt•tnt nl ~In..lh .Inll .lurerl .1. a. n in v ri.d v.lNUl.. Idltn~..rr.lr•, •Y:: 171-I~~, 1'1?i. 10. \Illlcr. I. .\.: (:In uN.gt•naa. rrt / lu•lnN,dt: •In ..a•l.n-em.. (.nNt•1 Rc... 1!1711, 11. \I/N.rt•. (:.: (:i);.lrt•nr •I/NIL/IIK .IINI I:urrr nl IIµ• IINNI/II, I/II•Ir\/1\ atul Lntnt. \ ttruliulunK 1'171. 12. Mrrlre, C.: StrNtlluq atN) r:nwrr td ,Ilt• nNNnh. Ilhanns :uNl Llrtnt. 1..\.\1..\., !9l:It17-1111, 1!110s, (S. Shalz.luv, S.: \hlltillh• Imnun' I-iINrr..tf IIN• IN•:MI :uNl nr.l I.nNI tvqdl.l`u.l. Iln pr...•) II. tiI.N.CI/u•r, 1/. t'.. St.M/IIIrYL. II. W, ,I/NI \tlNjl.l. \1•.: FH•ItI t•Ilrt•IV.IU.NI itn ..I.d t,1.ttiIN•J t IIi11N In/N1. l ar. rr. 1-1:,'1 IS. Srr,lnl. 1. R.: l.ll..l(rlllllr~l hw.i.~t nt 11K• I.r~l I.Itnt. (h.a. 1.11n. \. \tn.. 1:!N11- , 2INi. 1!1i:. III. \\\IN{Pr, I'.. I., .IINI ILdlm.m, 1).: I.dtNtn .ullt I.drrtrl \In..lr: lwullN•. in /%Is•t• nN•nl.ll (anin.eigm•IKVt \cw lurt. •\4.NIvmN Ih.v. Inc.. 1967. T:11 I I:IrrivNl .\tPn1/1' . 11wN/N1. ~LLCNIIUVtI.Ir.1IIHU1r. \'.InmIl.ull , C~~R HN 042>~ ~~