Document ykLnrm4qGxjXmeqzjQv7L0xEX

FOR THE STUDY OF TUBERCULOSIS ' Of THI EDWARD C TXUOEAU FOUNDATION Saxamac Lao, N.Y. February 24, 1943 KU l Mr. Vandiver Brown Johns-Kanville Corporation 22 East 40th Street New York, New York Dear Mr. Brown: ,, I have at last aucceeded In analyzing nost of our VQjCSalnous experimental data and assessing the resultsT) I realize that tfcla ahould have been completed before thla, but the emergency hae left oe short-handed In the Laboratory and aleo necessitated ay doing a good deal of extra traveling. I hope that the sponsors of our study of aebestoels will be oharltable and realize that the work has far exceeded its original scope. Vs have done over 40 different experiments, oany of . then-divided Into several parts, which Involved exposure of anlnals for 1 to 3 years to various dusts. The business of preparing nlcroscoplc sections and oheolcally analyzing the tlseues on nore than 600 animals hae been a Job in Itself. My tine for studying sections and analyzing data has been so United that ve are behind our sched ule. T have still not had tine to write a full report of this work which will of necessity be conographlc. However, for the benefit of the contributors, I an subnlttlng a table of contents and an an notated outline to Indicate conclusions and the line of argument that will be developed. The latter Itself occupies 15 pages, but I hope they will find it sufficiently Interesting to reed. I shall work on the final manuscript as I have opportunity. ' * There are a few experiments still In progress which should be coupleted by the tine we are ready for then. *he work on nethods.of dust deternlnatlon, I consider inportant enough to in clude In the study. The question of cancer susceptibility now seens ncre significant than I had previously Imagined. I believe I can obtain support for repeating it from the cancer reeeerch group. As it will take two or three years to oocplete such a study, I believe it would better be omitted from the present report. If It should become possible to nake this study, I hope that I any count on sone of your nembers to supply ne with enough pure, long fibre asbestos for the purpose. // il .s; ---=- . - e.- - - - *-- Hr. Vandiver Brown 2- February 24, 1943 Naturally# * shall velcone any oritlolan that you or any of the other contributors would care to offer. Should any of then want to dleoues details# !would bo pleased to oeet with then. May I take this opportunity to thank all the aponaoro through you for the support that ve have had. Slnoerely youra. UJO: =3H Leroy-U. Gardner, M. D. director L. (3) t (e) Effeota of Alualnua 7 Physical Properties in Relation to Irritation a) Length of fibre b) Cffeot of Crushing o) Heat treataent 8 Mature and Significance of Aabestosis Body (a) Foraation (b) Protective effect preventing further irritation (o) Ultlaate solubility in tissue 9 Theories of Action of Asbsstlfora Minerals (a) Cheoical - reasons for considering invalid (b) Mechanical - experlaental deaonstratlon of. 10 Coapllcatlons (a) Infection, tuberculosis and other varieties (b) Cancer of lung - experlaental data suggestive but not proven 11 Disability 12 Essential Features of Hazardous Exposure (a) Mature of dust - fibrous ooaponent and site faotors (b) Ataospheric Concentrations - probably lover than for quart*. 1 Inadequacy of standard laplnger saopllng method vhlch does not collect the dangerous fibres 11 Eleotrostatlo preclpltat**'sampling preferable bu* W> method aust be modified ' ' (c)`Duration of Exposure 13 Recommendations for a Mew Standard of Safe Ataoapherlc C centratlons of Asbestos Dust (a) The Quasi-official standard-of 4 to 5 million partlc per cu. ft. (b) Work upon better method of saapllng (c) necessity for comparison of results with X-ray flndi in employees 14 Prevention (a) Chemical aeane not practical OUTLINE OF PROPOSED MONOGRAPH ON A3BZST03I8 ... . ' . '. . Saranac Laboratory* Study under Grant from Asbestos Association f PART I HUMAN AS3E3T08IB 1 Human Pathology - a study of 2S autopsy cases, Illustrated 2 X-ray Patterns in Aabeetoeie, Xlluatratad 3 Aah and Mineral Values In Hunan Aabeatoala Complications of Asbestoals (a) Susceptibility to infection 1 Tuberouloua 11 Non-Tuberculoue Ill Cancer of the lung . 5 Disability, causes and comparison vlth silicosis 6 Diagnosis . (a) History of adequate exposure (b.) X-ray film pattern (o) Physical examination (d) Asbestoals bodies In sputun, their significance (2) part ii SagerAfrefltosia 1 Methods (a) Inhalation exposure to plant dusts. (b) Injeotlon into lungs through traohea of purs minerals. (c) Injection of pure olnerals into other organs. 2 Species Susceptibility Man, guinea plge, rabbits, oats, white alee and rats, doge. 3 Peculiar Charaoterlstlos of Asbes.tosls (a) Unusual looalltaion of chrysotile fibre in lungs. (b) Rate of resultant tissue reaction core rapid than to ouartt. (c) Reaction to chrysotile not progressive after exposure ceases; again the reverse of the situation in silicosis (d) Asbestosla Bodies 1 Coaposltlon and methods of foroatlon. 11 Occurence in different speoles. ill Formation does not parallel developaent of flbro'sl lv Oradual disappearance after exposure ceases. A Comparative Effects of Different Aabestlforo minerals. (a) Canadian Chrysotile. (b) Arltona Chrysotile, low iron. (c) Crooldollte 1 Bolivian speoloen, stiff and elastic. 11 South Afrloan, soft ar.d flexible. (d) Anthophylllte (e) Aooeite. (f) Tremolitp. 5 Effeots of Control Minerals (a) Orannular Serpentine, saoe ohealoel composition as .. chrysotile. (b) Class Wool, a synthetic silicate fibre. (o) Bruolte, a fibrous magnesiua hydroxide almost free of silica 6 Chealcal Composition of Aabestlforo mlnsrals in Relation t Irritation. (a) Nothing in composition correlated with relative lrrlta capacity. * (b) Preliminary acid treatment i Hydroohloric aoid* 11 Carbonlo aoid (3) * (c) Effects of Aluminum 7 Phyaloal Properties in Relation to Irritation a) Length of fibre ib) Effeot of Crushing o) Heat treatment 8 Mature and Signlfloanee of Aabeetoela Body (a) Formation (b) Protective effeot preventing further irritation \o) Ultimate solubility in tleaue 9 Theories of Aotion of Aabeetlform Mineral* (a) Chemical - reaaona for considering Invalid (b) Meohanlcal - experimental demonstration of. ' 10 Complications (a) Infection, tuberculosis and other varieties (b) Cancer of lung - experimental data suggestive but not proven . .. 11 Disability 12 Essential Features of Hazardous Exposure (a) Mature of dust - fibrous ooaponent and site faotora (b) Atmospheric Concentrations - probably lover than for quartz 1 Inadequacy of standard lmplnger sampling method vhlch doss not oollect the dangerous fibres 11 Eleotrostatlo preclpltata^sampllng preferable but method must be modified * * (c)*Duration of Exposure 13 Recommendations for a New Standard of Safe Atmospheric Cc centratlone of Asbestos Duet (a) The Quasi-official standard-of 4 to 5 million partlc? per cu. ft. (b) Work upon better method of sampling (c) necessity for comparison of results with X-ray flndlt in employees 14 Prevention (a) Chemical means not practical 1 Acldoala neoeesary to dissolve ribrs In lungs i than Aabastosls 11 Alunlnua Therapy Inapplicable 111 Chief reliance still upon dust prevention with speolal eophasls upon the fibrous oooponenta -I- A3BEST0ST3 - ANVCTED OUTLINE IKDICATISO RESULT3 PiRT I - HUMAN A3BE3T03I3 1 Human Pathology and X-ray Patterns - Description Baaed upon 23 human autopalea 2 Aah and Mineral Valuea In Hunan Lungs. 3 Cosnlloatlon of Asbestosls (a) Susceptibility to Infeotlon 1 Tuberculous- High lncldenoe in English experience cot duplicated In surveys of American Plante. Available autopsy atntietlce deceiving because of eelectlon of material. 11 Non-Tuberouloua- The aame reaeon probably appllee ehould be checked. by analyele of abeenteelam among aabeatoe workers. Ill Cancer of Lung - Ditto, but there are now on record 10 caeee of. lung cancer In aabeatoe vorJeera. Compared to the total number of autopalea on asbestosls, this lnoldence is excessive. Ko euch frequency hae been discovered in elllcoeia $r other forma of pneumoeonloale exoept^the Schneeberg mine's of radio active oree. The evidence la `suggestive but not conclusive that asbestosls cay precipitate the development of oancer in eueceptlble individuals. 4 Disability Clinical experience suggesta that truly disabling asbeetosla is manifested by leae striking X-ray changes than a corresponding degree of elliooela. Such disability in asbestoals is due to disease vlthln the lungs and not to secondary heart disease. As in silicosis, associated pulmonary infection Increases the amount severity of the dust fibrosis vith resultant accentuation of disability. There is urgent need for a' careful physiological study of pulmonary function in asbestosls of varying severity. Undoubtedly, there are many dlagnosable eases with no significant disability. 5 Diagnosis depends upon three faotora. (a) History of adequate exposure, usually 6 to 6 years, some times longer, at work where both the concentration and *x.t character of the asbestos* dust are hazardous. , . 7^ fc )- , * : : >8^5 .*}'!'*** * (*o) Evidence of disease*in a characteristic X-ray pattern. vljO :; -- (c) A physical jxaolnstlon vhich reveals certain characteristics- signs and nay reveal evidences of disability if present.. *~. r. .* (d) Asbestosls bodies la the aputun are oonflraatory vhen the -., previous faotors are* all positive. However, the bodies nay be absent/ particularly 1:. the abser.ee of bronchitis,'-/ infection. Asbestos'*!bodies unsupported by other evidence do not oaks ; .a diagnosis. Occasional ones have been found in about 15 autopsy specineno of persons with no known exposure and no fibrosis, probably'of;non-ocoupatlonal origin. :J && II Experlaental Asbestosls V* I Methods - ' r.. V .e (a) Inhalation Exposures .to Plant DusJ .-.Specific fibrosis.ln-^ lungs, but no ohsngee elsewhere. . .. > - - - *. ifriy (b) Injections of - Suspensions of Pure Minerals into Traohea:-^` Similar results. .. j .** >*.-V (c) Infection of Suspensions of Purs'Mineral into other organs . Fibres dissolved: no asbestosls bodies;.tissue reaction'con fined to phygooytosia and encapsulation. Conpare the -t f asbestos fastis of hunan-.subjects *-a/LV,~> . ..*.- ^ <**:-* n asjsiii au.e.jninVi -v Unlike free allloa,*asbeatos\does notjjroduoe its speolflo effet .in any organ of-any: speoies of anlaal.-^lt-oauaes flbroale oaly; the lungs of man and thoae of''a.^ev'of'the. speoles*tested. Soecles Fibrosis Asbestos Bodies-=8peoies* Fibrosis Asbestos-B* Kan 4+ ______* 4** If***-:* * Cat*. ~ guinea P_ig_____2_+________________ _R_a_b__b_it___- -- s* l*+ - very rVl stvrlcal asbestos WdlgaV-*_* _ . . ... '- - III Peculiar 0-------, 0T ( -3- 1 Fibres like bhrysotlle having a oertaln degree of flexibility and elasticity aorunulate within the finest air tubes; granular dust la oarrled further on and la widely soattered through the terainal air epaoes. (b) Rate of tissue reaotlon to asbestos Is ouoh more rapid than . to an aotlve dust like quartz. Evidences of formation appear as soon as sufficient oonoentratlon of fibres has localized *ln apeolflo areas; with quartz* there Is a latent period of months. (c) Reaction to asbestos does not progress on oessatlon of expos-'; ure. loung soar tissue that may have formed, oontraots and ; becomes core dense but the area of Involvement decreases in-:' size. In ellloosla, the-young nodules become larger after exposure oeaees. (d) Asbeatosls Bodies are a specific concomaltant of thla form of pneumoconiosis. They are due to a deposit of-protein and iron upon the surfaoe of Inhaled fibres. In guinea pigs they form after about 60 days of oontaot with the tissue. They are abund ant in can and guinea pigs, (See paragraph 2 above) but much larger In the former probably because the larger sized air tubes adolt larger fibres. In cats,- rabbits and mloe; there Is an atypical coating of a few of the fibres after muoh longer resi * dence in the lungs; In rats and dogs no bodies could be dls- ' covered. - From paragraph 2 It Is apparent that their occurence ; does not parallel development floroels. In lung Injection , experiment*, the bodies have nap developed untft after fibrosis le-vuall aorr.r.ced. The number of bodies seeos to decrease several years after exposure ceases. V CqmpflrfiUyg Si Different Aabestosla Mlqgrfllfl >;;-.v: (a) Canadian ^hrrsotlle - highly irritating. > (b) Arizona ^hryaotlle (low In iron) equally Irritating and pro- < ducee Just.-as many asbeatosls bodies as the Canadian product with over 11 times as much Iron. (c) Crocldollte - The South African blue asbestos Is known to cause ! asbestosls. Only a limited supply of this material In pure form was available, cost of it was usedearlier In the work In non-productive experiments. For the later critical Injection teste into the lungs, a Bolivian variety was substituted be cause of Its high purity. Its fibres were much atralghter, , j stlffer and core elastic than the cottony South African variety. : ; Perhaps because of these peculiarities, it has not given ;; reactions comparable to ohryaotlle. It produced asbestosls v ; bodies but did not localize in the terminal air tubes nor cause * any fibrosis. Teats now being repeated with a: typical South,; * | African crocldollte with physical characteristice simulating ;, | chrysotlle. I r \~ 'j fibrewstruoturoia proeerved.-ZITibres become" extremely- brittle^; '*** TThe physical ohange altera typioal localization'within thc*S??hi.r lung*, no flbroe4.* develops,-reaotionlimltod to.phyagooytoeLaV ? Ho aabeetoaia bodies" formed, .v `V; .yv . '^--r-v r*.. ^ i vT *'-**- ... *. Tin nature nnQ Signlfioanoe &X Asbestoels Bqdiofl *r. ./.r ... ` : -.rH-tviS-.'- (a) Bodlea. probably result froa dopoaltlonTof iron-and organic -- -* natter on a olovlydioeolving-fibre .of '.asbeatosi-v*The aouroe .. of the iron io nors llfcel7 to/be the lung tiaeue than the mineral itself as th coating is*Juot *ae*heavy*ron -fibrous .ninerale of lojf. iron-oontont.-oa upon. thoae*high.ia iron* /: * >- - 'K*-.**' (b) -.The affeot of aabestoais body'\foraatlon)l8v*aesu8od to be pro--j' tective although it has not*boea.poeelble.;to^ leolato a large v:; enough quantity of. these structures ; in .unaltered-. fora for .v-y purpoees of test*- The aaooth rounded-ends',presented-by the bodies would not'be neohanioally^irritating- *'?**' * $: .-..** &'* . * 4!f!V*,VWW ^ . *> - (c) If they were oapable of oauaing^irritation.xthe'fibrosis la the lungs should progress after exposure.oeasea which it doss not. . - ,^\* 'X'"'........^ -.*?:***- * *' (d) The gradual disappearance of bodies (andvflbres) long after ;* - exposunfjoints, to ultinate solubility in* tissue fluids. * i.- * (e) ^he bodies are probably a fortuitous conoocnitant rather than' *' a cause of fibrosis. IX Theories of Irritant Action of Asbestlforu Minerals (a) Chemical ^hese experiments do not oonflrn the theory that aebeetoeie is merely a form of silicosis resulting froa free silica liberated in the solution of a sllloate moleoule. If this were true asbestos,like cuartz^phould oauss fibrosis in any organ of any species for the experiments have shown that injected asbestos dissolves in these locations. However* it does not. c.uoe euch reaotion in any location but the lungs of * Ukt species. (b) Mechanical Irritation We are proposing the theory of mechanical Irritation which is manifestsd only in the lungs because this organ is the only one whose normal physiological functions involve a high degree of mobility. Experiments designed to prove the necessity for motion In this tissue have failed for technical reasons. For this theory to be applicable,it is necessary that the fibres be concentrated in the flare terminal air tubes. It has been.shovn that only ohrysotlle of the asbestlform minerals thus far nas the proper physical characteristics .to Insure such localization. It is also essential that the fibre shall perelet long enough before It dissolves in the.lungs of apeoles like nice, rata,*dogs. It apparently dioaoivee ao rapidly that it exerts no irritation. Similarly rapid, solution may explain In pArt, the lack of fibrosia In organs other than the lunge. \ -7- The fibre* must be long enough ao that they oannot be coapletely * surrounded by.phagocytic fella which would prevent contaot of these round, broken anda with the delloate cell* supporting the air tube*. Obaervation haa denoxiatrated that theoe condition* are realised in guinea pigs treated with long fibre chryaotile and fibrosis result*. With the other asbestlfom minerals that havo been tested, aooa or all of the prerequisite were lacking and no flbroaia developed. (c) If the irritation were chealcal, fine serpentine which haa the eane' chealcal ooapoaltion aa chryootlle should have alao cauaed flbroaio. The cruahed chryootlle shoudl have been more active than Intact fibrea, because of the greator ourfnoe area* ex posed to body fluids. On the aaoumptlon that chryaotile, like ouarts, beconea coated with a very thin layer of aluninta on treatnent with colloidal aluolnun hydroxide, capacity .to cauaa flbroaia ahould be daatroyed if the eotlon were chealcal but auch ij not the oase. (d) ^'he heavy coating resulting fron asbestosls body fomation ap parently doea atop tlaaue reaction but here the effects are probably nechanloal for reason* cited. (e) Heat auffioient to alter chealcal structure d eetroya power to irritate but it alao alters essontlal phyeloal characteristic that affect localisation of the fibrea in the lungs. X Complications (a) U8ceptibllltv to Infeotlon , dt/ih 1 Tuberculous - Aabeatoa behaves like aoat other nlneral/, in this respect and not like ouarts which specifically increases; native susceptibility to the-tubercle bacillus. This in- feotlon nay spread for a tloe but then heala. The reaultant flbrooia accentuate* that oaueed by the aineral fibre. li llon-Tuberoulous - of no greeter frequency than in animals Inhaling dusts of other kinds. Oocasionol epidealca of pneumonia occur in our dust rooaa, but theae are due to methods of housing rather than to dust; they alao occur in unexposed anioals. ill "- Cancer o? Lungq No experlaents were,designed to elualdate this point but certain evidence suggests that aabeat06ls aay actually favor development of tuaors in susceptible apeoles. 1 In guinea pigs, rabbits,* rats, oats and dogs lung tumors are rare. 2 When these apeoles were subjected to 2 to 3 years in halation of aabeatoa dust, the incidence of lung tumor ' v was not increased. .. * 3 Soce strains of white aloe do develop tuaors without apparent cause. j 4 Such a strain of white aice was unintentionally used in three inhalation experiments with asbestos* 5 Of 11 aloe inhaling long fibre asbestos for 16 to 24 months 8 developed malignant tunors in their lungs and 0 of then . had tunors in other organa, the lnoldenoe rate 81*63 is excessive. Of 22 nioe inhaling short fibre aobestoa for not longer thoi 12 nonths only 3 developed lung tunors* Rate 13.63 7 As oontrols. we have only the experience with aloe In other dust experinente. - *or short periods * there were 51 nice exposed to 4 th*r kinds of dust for 10 to 12 months. lnoldenoe of lung tumor 1.93. For lonr periods. there were 143 mice exposed to 4 different kinds of dust, lnoluding pure quarts, 23 to 31 months. . For all this group of mloe the average incidence of lung tumor was 13.83: the highest rate (253) was in a subgroup exposed to flint dust. Thus the incidence of lung canoer in the long fibre asbestos mloe was over 16 times the average for else inhaling other duets for eooporable periods and over 3 tines the oaxinun for any other*group Mice exposed to the praotloally inert abort fibre asbestos showed fewer lung tuaors although 7 tines mors than those in abort exposux to other dusts. *hese observations are suggestive but not conclusive evidence of a cancer etlnulatlng aotlon by asbestos dust. They are open to several orltlclsos. The strain of nice was not the sans in the asbeetos experloent as in many of the others olted; apparently the former were unusually ausoeptlbls. Rot enough aninale survived in the dust for longer than the 15 months apparently necessary-to produce many*tucors. *here were no unexposed oontrols of the same strain and age and no dlnllar oontrols exposed to other dusts. It is hoped that this experlnent can be repeated under properly controlled conditions to determine whether asbestos actually favor cancer.pf the lung. XI Disability Cannot bs determined in anloals. ^'he accidental deaths were from the same causes net with in all our dust inhalation experlnents. XII Ahe hatrda increase with the proportion of-lntnct fibre In the duet. Granular material and oruahed fibre are Inert diluent. 11 -The Ion* fibre oust be thin enough (1-3 Micron) and short*vJ: enough (under 50 Micron?} to be inhaled. ill Very short fibres (under 3 Microns) are practically Inert. (b) Ateospheric Concentration fltlll under atudy. Apparently this factor 1 lower than In the oaee of duets oooposed of granular ninerala tout aethoda of estlnatlon.are nls leading. i . I The average standard Fubllo health Servloe inplnger count In the long fibre asbestos dust roon'vas .40 nllllon particles per cu. ft. of air. zals'oonoentratlon;oaused fibrosis visible to the naked eye in 20 to 24 ninths. For comparison the average laplnger oounta in an experinent vlth purs ouartt vas 120 million particlea par cu. ft.'and fibrosis developed at about the sai n:e 'r*atm a.m ... s II However, inplnger oounta are deceptive baeauae by this nethod of sampling very fev fibres, vhlch are the significant elenenta in the dust are oolleoted. ; : * 111 Sampling vlth an electroetatlo preoipltator Is a much nore efficient means of collecting fibres from air-borne sus pensions. Samples froo our long fibre asbestoo room shoved that the dust In the air oontained 32.5* of fibres fev of vhlch had been oolleoted or oounted in the lmpinger staple. The latter eanpled largely the inert granular parti cles. . * iv As ordinarily employed preoipltator samples are weighed and the results expressed in mg. per cublo foot of air. There la no means of converting such values Into numbers of pertlcles particularly when these vary In sits, shape and `apeciflo gravity. . V * ; * *. >* * v Simultaneous saopllng with preoipltator and standard la plnger yielded the respective values of 0.65 mg and 60 mil lion partlolea per oublo foot of air. - vl `hsoretlo&lly the best Index of hatard vould be either the number or weight of fibrous elements in the dust. 1 -10- (c) Duration of- Exposure A/ +1Vt- . ; i Fibrosis visible to the naked eye after IS conths exposure. Increases in extent in subsequent 13,aonths. ` :v 11 The scan of Ilfs of our oost susceptible laboratory aniaal, -the guinea pig has prevented continuing bxpoejre longer than three years. In this period only the comparatively early stages of'asbestosls have.been-produced.* With the know ledge that we have gained. It lo probable that nore extensive disease could h&ve been produced with a purer long fibre -chryaotlle. The long lived species,-like cats, dogs are un !&v- fortunately not susceptible*:- . , : * * .* ill ' For these reasons X-ray ohanges have been nlnlnal and ve were not able to fulfill one of the objectives of this pro** Err. -, fr[e5'x-x; xi KIft*tly'V. ^ *. l gram. ... ^ - v :i- -. . 4 t** t * *f * # ** Rcon.T>endstlon for` New Standard o Safe Atnosoherlo Concentration of.Asbestoo i>ust. . ' <5*.. . . .* *i & ' While there la no official standard, the`tentative one of 4 or S alllion particles per cubic foot .-of air le frequently I r: fc\-* V.-r. i; Quoted. *- * , v* Or) This Is probably unreliable because It ;ls'based upon sanpllng with a standard lnplnger which we havershown does not collect ncsf of the fibres that are the source of.-hptard. ` * . *'' (c) We now think that a standard should be based upon sanples collected with an electrostatio precipitator If It Is feasible to deteralne readily the relative proportion of-fibres In such arterial. :? ':+*.. ,, :V T'.' (-) Work lo still in progress upon-the latter-polpt. . 'w . (e) To be of-value the* new standard vould.-hayei-to'^be correlated with the'-'X-rey findings-upon*enployeea.'.expbeed;to different concentrations of dust. * # *yV .* ` RV. XIV Frever.t iso a ataoili-' .1* . W,*.. e-..'Sa., ^ The experinento have fai led .to*`de. velop .a-nyJ4p.' *rac tic:a l'c*heaical ' uesns of neutralizing the action*of fibrous J'asbe'ctos.-. *.- .1 . ' 5". *. ,T` - v \\? ;-' v * /?: (a) To alter the :hunan*lung so' that It vouldTdleaolveyaastoe s to 8 fibres rapidly likee a rat would necessitate: (ysebub^y? J! creating an acidosIis the flbroele. wh--loAh w%o* u:ld bsysorse .than othe effec te of ;**.- * a r. ?% #. V^pa. . /_ f* .:** :*>r.J4tVa\j*Ti-.-*4--.%*#^v*---ly' * a*.-* . > . ., If. - '-'i * .. I t V. - * .r . V.. * ^ V v`* -1 ** * _.r ? :: -\ gi*.'' ' "V * -3u**-`:>'%* ; v'*'- z*l: 4 l* . - J **.