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I. Exp. C1in. Cancer Res.. 3. 3. 1984 Gt~ r*AkVA Tcs> ts passive smoking and added risk factor, for liung cancer in -Chinese women? L.C. NGoo t' Pin,O., J.H-C. Ho` M.D., D.Sc:, F.R.C.P.,, F.Ri.C.R., D. Sauv' F.R.C.P.A., M.R.R.C. Path. t Detxrrtmtnt of Communiry Afrdicirte, tfninenity ol Hong Kong, Hong Kong s M. & H.D. Institute of Rudiolotlv, and Oncology. Queen: Elirabtnh Hospiral, lfong Kong S,Sf. & MD. lnstirute of Pathology. Queen Efizo6eth 6lospttal, ffong Kong 2tx1 female lung cancer patients and 200 healthr district controls were inter- viewed to identify and quantify, the various sources of passive: smoking among Chinese: females In Niong, Kong. For the ever.smokers; passive exposure from external sources did not appear to add' to their riuk. For the nevemmoken. qualitative assessments (smoke expol eategorif:s, age when passive exposuree started), and'' quantitatiire assessments (hours, years, lntensityJ' showed no si, gtsificant differences between, the data for patients and controls. Moreover, higher relative risks were not associated with higher leveis of passiive smoking for the ever or never-smoken. Thus, our findings wouid seem, to indicate that passive smoking, as an isolated factor, did, not have an influence on female lung cancer incidence in Hong Kong.. Recently, there has been renewed di- scussion on the possible ef fects of passive smoking on lung,cancer risk (5, 8, 19). In previous studit:s on the possibility of' increased ri'sk of lung cancer among wi• ves/husbands from their smoking spott- ses, the data (2. 9, 12, 16) were only basedd on whether the spouse smoked (yes/no) with no further qualifications on whether the smoker actually smoked in the pre- sence of the sub jet:t, and for how long~. Where • quantification n was done (5; 17, 1g), it was baseti' on the current spou, se's smoking habits. It is well known that the carcinogenetiic process of internal so- lid cancers usually begins 20 or more years before diagnosis when there might have been no exposure from the current, sour- ce. Furthermore, little account was taken of changes in smoking habits or marria- ge„ or the possibility of exposure from the work environment., Some of these pro- Received January 14', 1984., ' To whom requests for reprints should be unt: blems were raised' by Hammond and' Se- llkoff (11) buit they have yet to be ad- dressed by epidemiologicat studies to date. Chinese females in Hong, Kong have an average artnual agt:-standardlzetii inciden- ce rate of 24.1/100,000 for lung cancer (113). This is among the highest rates [or women in t!he world. In ordk:r to more directljr assess the possible role of passive smoking in lung cancer deveiopment, •a retrospective study of 200 female lung cancer patients and, 200 healthy district controls was begun in 1!981. Hbng Koa¢;, with an average urban, density of 28';0G0'i inhabitants: per squtare kilometer, and 3'. m" of average living space per person, is one of' the most densely populated areas in the world. It is; therefore, an appra priate place to test the passive smoking aetiological: hypothesis. Patients and methods The 200 lung cancer patients studied were from the wards: or out.,patient departments of' 8 hospitalk 277' N I i 1 4s` ~ ~ : i

.Ia .. . - . , + ~t,~,,el~lgt~i. tCuo L.C. ul afL in Hong Kong. Patients wera lntervfewad atr thcy, becatru5 available. Eiitht possible subjects were not interviewed because' they were ttot, wfficiently, alert to answer our questiorts: Attother l!' tiad i to be excluded after interviews had' been (:aapleted, when later, evidence and checking ' revealed that their lunag tumours were secondaries and; not primarics. Medi- cal records and radioaraphs were: reviewed' by /.H., C.H., and pathology sptroimens: were' verified by D3.. w,ith' her wlleat;ues. Where necessary; additional dia- gltostic procedures were requested to complete the data., Patients were matched with an equal nttmber of healthy controls by, age straiif)cation (t S years) in each district In = i4h and by, s(7cio+economic, status. Conirols' were interaiewed, at their homes within a, f'ew weeks afier their matched patients had baen idt;ntified. Two ferrwle research assistants, fluent in, Chinese and En,llish, conducted the interv,iewt(' using a tape rccor&r and, semi+struetured questionnaire. Wtiliziny Interview techniques from the social, scienees„ espe- cially thosu related to the gatherins of' life hislo• ries, thu interviewers were trained to probe for detailt and eleboration, of' facts. Data were obtai- ned on the changes in, residence patterns since birth (where liived, how Ibn`„ how many toYether, what type of housins. how many roorns)p occupational • history, (where worked„ what done:, level of pollu• tion, how lonp); active' smoking , (type of' tobacco, method (+t smoking, and amount currently smoked and at 10. 20. 30. 40. 50 or rtara years aYo„ and inhalation prsctices):', passive smoking (from whom„ what u)pe of toba4co, product, amount they proba- bly smuWed' per dhy;. amount of time; of exposurc„ when sropped, or chan(;ed1:, personal' and fumily' hi- s(ori.s (a6e ot marriaQe, divone, separation, andJor widowhuodk number oi :hildren, oceupations of' pa, rcnts and spousc): etc. The', taped interviews weree transcribed and then checked by (1.C.K. for points that hud been left out, or for incronsistencies, e.g. comparing passive smokin; exposures with nesldps, '' tial and marriage histories. Where neeessary, su¢ jpcts were: recontacted' for fttrther' inforrnation. The mean age of the patients w,as 611 years tS.D. 1'0.0)' and that for the controls was 601years (S.D. 9.6s: Rirsults Histological distribu¢ion'. The histolbgical distribution according to WHO 2nd! Edition (20)' and basis of diagnopis of' the patients are show°n in Table I. The predom'inantt cell type was adeno- carcinoma, forming 34.5% of the'total sam. plk, or 38% of those with histological t'y- ping. However, when the frequencies o'f' sqvamous plus sm'all celli types' are com- pared with adenocarcinoma plus large cells, the resulting, Kryberg ratto (6) of 1.16 still showed' a preponderance of the former growp of' ttimours. This low rela, tive frequency of adicnocarcinorna's in Hong; Kong Chinese femalzs was also fount!, byChan' and MacLennan (3'T. Smoke exposure caiteguritss From our lrlite'rvleWs', thirCe major regu+ tar sources of tobacco smoke were identi, Table l• Cr(( ryp,c+' und basiso/' diugnusis. C6:11~cype, S~quamoue~ Sma11. ce('1~ idan- cA^• ^^^- , Grge~, eelll Mixed Carclno:id~, Unei.e- ent'led rocal. No.. (.) '. No.. (1)~ No~. lS)~. No~. (.') No,. (!7,) No.. (S), No. (L)! Fo. (S)I aroncho.copi~c blop>y' Aasecc~.on l:ympR.h r.cde Pleur+l~~ 26~ (1'J.O) 1(. )..0)~ 9('. +.S)~ - 14 (.1..0). 7(~,3.5)~ •. (~~ 2.06 1. ( OM 9~( 4..5)~ 33 t0 (~. 5.0) S(~ 2.5) .( 2.0) 3(.1'.5) 2('. 1.01 2(: 1.0) 3(. 1.5) 3 (~, 1.5) - l ( 03) 9~ (~ G~.5'.Y 1 ( 0',.5)' -~ 1 (', 0.5) 65~ 6'2 25~ 9 (.L".51i (3'1,..) (1'2~..5)~ ('t.5) Spucuo cysolo,}y~ 7~~ ( 3,3) 1'L ( S'.SY 12 (~ 6~ 0.)~. 1. ( 0~,.5): -. 1 C o:,SD~ 32~, (16.0) Itedtodugdcal~ S c('tndca~l. - _~ - 7' ( 3:5'), 7~ ( 3:5')1 Tuc..,t. 56 (2k~.o)i 37 (1ig~..5)~. 69~. (34'.5)~ 1'L (. s'..5) 7(, 3.S)i 1( 0.5')I 19! ( 9,.5) 200 (100 ), ' f4j.le.Jao rruna0runehwf oluyvr. 278

s':W'!$ffii ,' K':'. . •"~`'-` s . Passive smoking risk in Chinese womtn."' fied. In addition to ever-smokers (S), there ve smoking at home (H'). workplace ('W). were those who had cohabiting relatives or' both' (HW) had RRs only marginally smoking in their presence at home (Hk;. or those daily exposed at their workplace for a number of'years (VSr): In Fig. I three intersecting circles have been dt•awn to Table Iil! • Rtl riaks c•arrY~ries. f RRJ I Jrnr di IJerertr exposu re shown seven possible categories and one " sl"x`• `•'"r°``'•' IN„I isolated circle (N) representing those who had never bec:n' exposed to any of these [xPP•ur..a,c.4arq, .r.cd.nc'a concro't•. U regular sources., Passive exposure' is dc nuted by the shaded'' area. and includes o:ei~ sidiestream' smoke from home or work• sa' _ 6? ~6 2.se . ~ , a'Y place. sNN'_ ts 2 3:9b Tolsie whether this qualitative method • N 22 4'a t.oo of assessment would discriminate higher risk groups, all patient's and controls we- re fitted into each of these 8 different smoke exposure categories and the odds ratios were calcul'ateti' (Table II). If those liming', none (N) rt:present'' the sta'ndard! with a relative risk (RR) of 1.00, smokers with no, other source o'f' exposure (S)' or rnubtiplb sources (SH, S'W, SHM' had RRs ra!neing from 2.56 to 5.45, whereas no'n= smokers who were': only exposed to passi- I ~ Ever smaked i . .' Passive e:;posure,at $rruat;e . expurure, cuia.runra. Tooat . rat.{octrr eo.ptp.e. tsp,o.ur.cacriory. S:'n SH SL.f SNV N r. 4~ NL N Tocal ' v s u,uvw! Passive exvos'~ure a't ho'ar.e ., r --'~,t"{C (l~l.ilce. r# ~~..' .. .. . .~ . ... ~1. ., . .. . . :oo ruc.au l12 66 22 No exposure cLain'ed Z 1 C` w 8 g. Gr h4Tj'7. --- 279 lV v ll 00ut. N o C~ mr(~ too coocroD. 63 97 co' ax 3.23' • 1.24, 1.00 200 / 661 77 Z2 ~f ~ °t 2 I9

greater than h00 =(range 0:91-1.59),. When Since about 90% of the total amounts smokers and those only passiively, ezposed, of passive smoking came from the hotne. were grouped' (Table' IIB), the RR of acti• Table IV shows the al•erage' contribution ve smokers was 3.23, and that for the' pas• from each cohabiting relative who smoked sive smokers a non-significant 1.24. in the presence ofthe subject. Only, ddirect Qursntiliiccttion of passive smoking Our detailed' interviews allowed' us to est!imate the amounts of passive smoking from various places in terms of hours or years (Table III'), Smokers as a group had more exposure to passive smoking from others than the never-smokers. De- pcnding on the unit of measurement, whe• ther hours or years, we found that among the.smokers, the patients had more hours of txposure, but the controls had more years. A'mong, the never-smokers, the con- tro15 actually had more hours or years than, ttie' patients, but these differences were minimal. Hours per year was used as a measure of intensity of passive expo- sure. ©xeralli there was no significant difference in exposure levels between pa- tients azld! controls, whether they were smokers or never-smokers. ~ Table III - .Average accumulaeive passive tobacco smok'e exposure by place. e6r sor.r• For navar-..or.r Table IV - Sourog' of passive exposure as home. 79 52 66 99 prciants controli,paci.ncs acncrol4~ ;~ 1. H.Dw 1:ours 22.773 21,.517 Y.~are 2D,7 31!.3 It. Voraplae• Hour., 6„352 1„867 Yacrsi 3.6 .:~ ..{ I21.-uca1 amounc. tw.aa 26,703 23,385 Yearo. 30.0 32.6 nuura~rs~r956.6 717.3 136789~ 16,526 25.7 23L8 2~~.,121 1,6811 2.3 1.2 17,.662 20.057 261.4 26.3 677:1 762.6~ exposure was counted. Husbands who smoked, but did not expose their wives to passive smoking for various reasons, such as living overseas, on travelling jobs; etc., were not included in the estiittations. From the Chinese cultural practice of ha- ving extended familly members living to. gether„ the female could be exposed to her parents' cigarettes or pipe when young; to her husband's and in-laws' tobacco du• ring; marital life, and to her children's ci- garettes when old. Although in terms of hours/personi parents 'were found to be a, heavy source of sidestream smoke, only it minority of patients or controls were so exposed. The most frequent source was that from the husbandl About 2/3' of the total hours of tobac- co exposure were calculated from our data to be from the husband's ci-arettes: Both cases and controls had an avera'ge of about 20,000 hours of passiti•c smoking from, their homes; so that no signi6i: ant difference in exposure levels was found between them. A'vera8a cocal. aaou1r. 14'1patwc. ON.eonerols No. itours/p.ri.oa :lo. HeursJp.raoo liusbrndi I113 16;183' 11!l 19.314 B.rancsi 18. 27',994 21 27,7ti' In-la.c 7 28,1'37 6 9,177 Ohlldr.n 24 3.604 33 4,170 Ocorrs 9 11,333 13 4,33'6 Awra6 • for a11 215026 20,672 p < U.YU ' E:..r..icd pro,e 37 pulirnrs and 11 runfrols wi/l,, out l:"asive exposure. 280 "~'.'r~-,~r'w~"'1`"`. -'±r--"K'~~,~*',~"~,~ --w~* ~ ...-- ~ M1S'+' t_' v~" c~ i ~: M trC . . 4 i ....-.. . , . . . . . . ' . _ ... _ . . ~/..

, Unlike the Louisiana study (5), we found no association of an increase in disk of lung cancer among current smo.• kers, ex-smo'kers, or never-smokers andI material or paternal (yes/no) smoking, habi!ts. Passive smoking risk in Chinese women? Table V I- RJt'_ ol ' lun g, cancer among nemer-smokers by levrrs of puuive exposure. 9 C.wgocy . Mctsc. Ca6tsoLd }t t vatw )ba. 22 40 1.00 tbv' 37 eit 1.29 1& 0..6 N18p=' . 9. 116'. 1.02 410.96 towi' y.r.tv. 66 ' 97 1.24 60.49 Sunoking, history and' histology ' S 33.UO0 hours Annong, the ever-smokers, there was a"> 3s.ooo hours predom!inance of squamous and small cell types of lung, tumours, whereas the op- posite posite pattern of a predominance of' ade- nocarcinomas was found for those passi- vely exposed and the N category (Table V). There was no significant difference in cell type distribution between' the pas- sively exposed' women and those with no, regular exposure. The predominance of' :nocarcinomas in the never-smoked women as a group, regardless of their passive smoking history, has been repor- ted elsewhere ('1, 4, 10). Table V- Smoking hislory, und histoJoYy,. C.ll~~ cyip.~... SsoLtnBM1lucory, SQv..ow.r Si.ll C.ll Ad.nocaner.noea... L.rg. f.li1 Cva ~.sot.d 647.~.(61/96)~ 36% (34Y95'.): lr.rtW.~.wkin8 i21~.(25159)~. $81 (34/59.)'~. Hoo. 37L~.(I7/19)~. 6Ji (12J19)i Risk among never-smokers We have earlier shown that the average total amount of hours or years of passi.C' smoking amon!g, the never-smokers wass not significantly different between pa- tients and controls. We also did not findi a higher RR among patients witll, passive exposure levels of > 3Si4U0 hours (3 hours. 12 trlin./day x 30 years) than thu-_- wiithi luwer exposures (Table VI). It is possible that the bronchial mu- cosa-s is more susceptible to carcinogenss before adulthood than ltlter in life. Table VTI summarized our data on age when passive exposure' started for the never- smokers. There was no significant diffe+ rence between patients and controls in their ages at first exposure. In fact, there were more controls who,had been exposed' before the agF of 20 years than their mat= ched patients: Thus our data were unable to substantiate the possibility raised, by Doll' and Peto (7) that a life-long, exposure (including childhood) may have four tli, mes the effect of exposure which is li- rnited to adult life y. T•rbte Vil - Age pnssive erpoaure siur(rd /or nevrr- smokers. r.cdanu. Concrols Ke No. (Z)'M tlo. (.)~ 0 20~ - 191 - 39~. 13 42 (2]D (6t,) 30 50 ~. (31')~. (5=)~. G0ir 9 (1;) 17' (1d). Towl, 66 97 ' Av.rr`e a8* 36.6' 34.3. PS0.1U. Risk for ever-s»tokers It is well established that n(lt (,dl' su7ru- kers, not even heavy ones, will develop 281

<., . .. . . ..~. ~~ - k i. ~. . _ . . .. . _ -.,. AW ~ t..C.. r.t'~. OfL lung', cancer. To see if' passive smoking adds risk to active smokers, the risks for lighr smokers (< 100 kg tobacco' or 1/4' pack years), with low or no passive expo- sure (< 15,000 hours or 1S hours/day x. 30 years) and those' smoking, similar, amounts but with, heavy passive smoke exposures. were compared (Table VIIII). The same comparison was applied also to the heavy smokers (> 100 kig or 14 pack years). We found not only no increase but an actual decrease in the risk for both light' and heavy smokers with heavy pas- sive exposure compared to, those with no or low exposure. There was only, an, irtcrea- se in the risk related to the levels of theirr own cigarette consumption. This result was also found by Correa et a'1: (S);. Table Vtllil - RR lor smuksrr with und' witJiuut pussiLw ex~poiure: Tryp. t,6eL.nes ConeroLr L1l tSgho smok+rrtOch, lbv: or no~.aaposur., 1'~b esgp'c cmokerr vbch h\av"/J~ s~~U,~LL[i ~ Naavy, .wk.raa'vtth, lovior~no .aposur.~, «~. Nravn..ook.ro~vurh~ 19 t.00 1;7 0.:c lY. J.62 h.avy..xpo.vr., L'SI U 2'.61. Toca i. 1'12: 63 ' s 10(1 kji , tobuccu '' < 11000 hours > t00ik`,tobarru " >_ 15,000' hours' ©iscussion' In this retrospective study on the por sible in!iluemce of passive smo'king', on che high, incidence of liang, cancer in Hong Kong Chinese females, we have attempted to identify andi quantify various sources and typas of tobacco exposure among 200 patients and' 200' district controls. We have l'imioed ouir data presentation to show on- Iy rh'o~.c (.,ctors relevant to the issue of passive _,+iiul:inb: A more detailed descrip- tion and. discussion of' active smoking as 282 a risk factor was presented elsewhere (15'), The apparent lack of an' association benveen, passive smoking and the risk off lung. cancer in our study may, be due to possibilities which occur because pa;ssin•e smoking may be only a very weak carci-, nogen, whose effect may be concealed by other factors that play a role in a mul'ti- facto'rial and' mul!tistage aetiology, Among, the female never-smokers, intervening factors might cause an overshadowing or a protet:tive' effect (e.g. bronchial irrilta- tion, dietary nitrosamines or beta,carote- ne): These factors in Hong, Kong ace li•, kely to be different from, those in Japan (112),, tU.SA. (9; 16), or Greece (117; 18), and this difference may explain our d'ifferentt results. The possibility that the a d'ose-re- sponse curve resembles a ltngistic in sha- pe , such that t there is a dose- greater than zero which produces zero rt:sponsa D was considered by Hammondi and Seli- koff (i11). and'i may be: operating hert.. Certainly the lack of an increased risk for the' active smokers from passive stno- king; which was' also found by Co'rre:, et al. (S). Would seem to support the pessi- bility that the effects of active smoking or, indeed, other factors yet to be iden- tified, greatly overshadowedi the carcino- gen!ic action of passive smoking. This„ however, dbes not iinply thac ras- sive smoking is innocuous, as it may con- tribute an added risk of'othzr respiraitcry, and cardiovascular diseases (8, 14', 16). The possibility of other factors like diet. previous history of respiratory diseases, occupational exposures, use of' inhalants, etc., overshadowing or inhibiting the et- fects of passive smoking on, the risk of lung cancer among never-smoked females in Hong Kong and also' the roles of' these factors in the carcinogenesis are being' investigated. I't is hoped that more direct a'sstss, ment ot' passive smoking by orher «•or: kers in other areas can' shed mo're aghit on the passive smoking controversy.

AkrrowfldYemants' We wish to esptnsa our gntisudt aod thanks to the (ollowing insututions andl individuals fur their help in this proieet: the Hong Kong Anti-Ctncer Soa:iety: and the Researcls and Conferettce Grants Committee and the Medical Faculty Research Grant Fund of the Unineraity, of Hong' Kong for Gnancir,ll support; Professor C.K. Mok. Dn: W.K. Lam. K.K. Lu, Mry Wci; W:C. Chan, L. Hou. S.H. Low. K.W. Ch•rn and K.T. Tham and' Siater M. Aquinas for, theirr advict and help; Mr: C. Chan,, his. C: Tong and Ms. N. Lee for help in data. collection and analy- ais: and Ms. G. Lau. Mrs., T. Lam and! %41t: A. Chow for secretarial assistanue. References 1. Chan, W:C:. Colbourne M.J.. Fung S.C.. Ho H. C.:: Bronchial cancer in Hqng Kong 1976~.1y77'. Br. /. Cancer, 39:: 1!82•t92, 1979, 2. Chan W.C„ Fung SC.: Lung cancer in non- smokers in Hong Kong. In: Grundmann E. (Ed.). C•rncer Campaign, vol. 7. Cancer Epidrmiology. StuttgartJNew Y'ork: Gustav Fischer Verlag,, 199. 201. 1982. 3. Chan W.C.. fWacLennaa R.: Lung c:mcer in Hong Kong, Chinese: mortality and hiainlogical typcs; 1960:1972:, Br. I. Cancer, 35: 226-231. 1976. 4. Cuoper D.A.. Crane A.R.. Boucot K.R.: Pti- m•rry carcinoma of the lung in nonsmokers. Arch. Environ. Hbaith. 16: 398-.s00., P96x. 5. Correa P.. Pickle Ii.W:. Fontham. E.. Lin Y., Hacnszel W:: Passive smoking and lung cancer. Lancct, ii: 595-597; 1'983. o. Doll R.. Hill A.B.. Kreyberg', L.: The signifii- cance of cell type, in relation to the, acuology of lung cancer: br. I: Cancer. tt: 43--ttt. 1957,. 7: Doll R.. Peto R.: The causes ol', trnccrc quan- titative estimates of avoidable risks ut cancer in the United, States today. L, Nau C.nccr linst.. 66: 1192-1308, 1981. Passilvc stnokina risk in Chinese women?' 8. Editorial: Pauive stnoking: Forest. Gasp and facts. Lant:et, i: 34&349, 1982. 9; Garftnkel La Time trends in lung cancer mor tality among ttoa-smokers and a note on pas- sive smoking. 1. Nat. Cancer Jnst:, 66: 10611- 1066; 1981. 10. Green I.?.. Brophy P.: Carcinoma of' the lung in nonsmokina Chinese women. West. (: Mcdl. 136: 291494. 1982: tl. Hammond E.C., Selikoff LJ.r Passire smoking and l lung cancer with comments on two new papers. Environ. Researsh, 24: 444-452; 1981. 12. Hirayama Tu Non-smoking wives of heavy smo- kers have a higher risk of lung cancer: a study from Japan. Br, Mcd. 1.. 282: t83+185; 198L 13. Ho ).H.C., Chan C.L.. Lau W.H., Au G.K.H:, Koo L.C:: Cancer in Hong Kong: some cpide, miological obsernations. Natl! Cancer Inst: ktt} nogr:, 62: 4743, 1982. 1+4: Hugod C.. Hawking L.H.. Astrup P.: Exposure of passive smokers to tobacco smoke : eonui+ tuenta. Int. Arch. Occup. Environ. Health, 42: 21-29. 1978. 15. Koo L.Cc, Ho J.H.C.. Saw D.: Active and pas- sive smoking among ftmale lung cancer pa- tinnts and control in Hon;l Kong. f: Exper. sr Clin. Cancer Rrsearch.,*: 367-375; V983. 16. Miller G.H.:, The Pennsylvania study on pu.- sive smoking4 .1. of Brea[hing, i l: i-9: 1978. 17. Trichopoulos D.. Kalandidi A.. Spnrros L.. Mac Mahon B:: Lung cancer and'. passivc smoking; Int, 1: Cancer„ 27: li. 1981. 18. Trichopoulos D.. Kalandidi A.. Sparros L.: Lung cancer and passive smoking: conclusion of Greek study,. Lancet, iii 677-678; 1983., 19: U.S. Department of Health and Human Servi- ces: The health consequences of smoking: Can- cer: a~ report of the Surgeon General. WashinQ- tonl D:C.: U.S. Public Health Srrvicc. 1982. 20. World, Health Organization: The World Health Organization liistological' typing of' lung tumourn. 2nd Edition. Am. I. Clin. Path:, 77: 123-136, 1982. 283' ! i'. I I { i z; f r