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ReÐ.Inst. Med.. trop.

Stio Paulo
29(5): 305 311, se¿e7¡¿bro-outubro, 1981

EFFICACY OF OXAMNIOUINE, PRAZIOUANTEL AND A COMBINATION OF BOTH DRUGS

IN SCHISTOSOMIASIS MANSONI IN BRAZIL

K. ZWINGiENBERGER (1), J. A. NOGUEIR,A QUEIROZ (2), U. POGGENSEE (I), J. E. ALENCAR (2), J. VALDEGUNAS (3). F. ESMERALDA (3) & H. FELDMEIER (T)

SUMMARY
combinâtion of oxâmniquine (7.5 mg/kg) plus prâziquantel (20 mg/kg) against either agent, oxamniquine (15 mg/kg) or praziquantel (40 mg/kg) alone, in the treatment of schistosomiâsis mansoni in the Brazilian north-east. The drugs v¡ere rândomly administered per os to 91 patients. Six and twelve months after treatment 89% of those admitted to the trial were reexamined by Kâto-Katz method (ten slides) and MIF technique (one gram ofstool) The achieved cure râtes, âs defined by absence of S. mansoni eggs in the faeces of individual pâtients at alt points during the parasitological follou¡ up, v¿ere 8l.gvo, 81.2% and 67.6Ea for prazíquattel, oxâmniquine and the combination respectively. The reduction of eggs excretion in non-cured patients six months after therapy
ran ged from
93

A rândomized clinicâl trialÏvas carried out to compâ¡e the efficâcy ofa low-dosage

.8-96.8% wi th prâziquan tel,32.5 97

Ea

urith ox âmniquine an d ? 6.9-99 .59.

v/ith the combinâtion. It is concluded that, at the used dosages, the three therâpeutical regimens give similar ând satisfactory results in the treatment ofuncomplicâted S- mansoni infection in Brazil.
KEY-WOßDS: Schistosoma mansoni; Oxâmniqui¡e; Oxamniquine resistance; Praziquantel.

INTRODUCTION
Two compounds â¡e currently recommended for ùhe treatment of schistosomiasis mansoni52. Oxâmniquine has been used in large scale mâss l,real,ment in Brâzil, in an attempt 1,o curtail the transmission of this helminthiâsis ând to achieve eradicâtion3o 45 43 5r. ïrhe drug was advantageous from the point of vie\tr of cost-eflecti viness, since satisfying cure râtes have been ac-

complished in this country with a single oral do. mg/kg body weight33 40. fn contrast, doses up to 60 mg/kg are required in Africa to attâi¡ similar therapeutical efncacy in schistosomiasis
se of15

mansoni3e. Oxamniquine is usually well tolerated35 a'z and clinical imÞrovement has been observed in advanced cases of this parasitosis3 '3.

Nevertheless serious central nervous adverse

(1) LatrdesiDstitut i¡r Tropenmedizin Berlin, {¡est Berlin, Federâl Republic oIGermâny. (2) Núcleo de Medicina Tropical, Centlo de Ciénciâs da Sâúde, Universidade Federâì do Ceará, Fo$âleza, Ceará, Brasil. (3) Sì¡perintendência de campånÌ¡as de Saúde Pública {SUCAM), Ministélio da Saúde, Cmto, Ceârá, BmslÌ. A¡laltcss for conesDoDrlerce: H. Feldmeier, Depårtment oflmmunodiagnosis ând Immunopârâsitology, Landesinstitut fr:r TÌopenmedizin. Königin-Elisabeth-Stlâsse 32 42, D'1000 Bedtx 19, Federâl Republic of Gelmâny.

: NOGUEIRA QUEIROZ. It proved to be a safe drugca zs :e -n has been "n administered to schistosomiasis pâtients with hepatosplenomegaly without inducin g any severe untoward effects'r 13.I ALENCAR.3¡. presented the uncomplicated form of the disease. Tabtets of both drugs were used in âdults.rs. Fewer than 100 eggs per gram were encountered in 279a of the individuals. mg ofstool). sis of faecal egg counts using the Kato thick smear technique as modiñed by KATZ et al. In such event it may occur The mâi¡ characteristics of the patients en rolled in the three groups are shown in Table I. egg. The overall mediân numbe¡ ofeggs per gram ofstool prior to therapy was 168. produces a synergistic action âgainst S. Moreover. In âddition. São Paulo. range 42-964. were diâgnosqd as infected þy S. situated in the interior ofCeara state. lne worm bt¡rden was quantified on the ba.R€v. prâziquântel and â combination of both drues ìn schistosomrasis mânsoni in B¡azù. oxamniquine was administered in the form of syrup. K. taken simultaneously. (b) prâziquantel 40 mg/kg in two split doses. They did not differ in age or sex composition. mansoni in a parasitologicâl survey. The median age was 21 ranging from 10 to 62 yeafs. This methoqôlogy was bâsed on the rationale that a single Kalo thick smeâr reliably indicates the intensity of infection only if egg excretion is highet than 50 ova per gram of faeces. PATIENTS AND METHODS A total of 93 subjects living at an area endemic for schistosomiasis in the municipality of Crato. H.¡as no significant difference in pretreatment worm burden. Such resistance hâs been confi¡med by other investi gators'z re æ' 41.: VALDEGUNAS. and Mann-Whitney signed -rank test to compare reductions in egg exc¡etion. in children.24 Í¡ith praziquântel and 3b received the combinâtion. and (c) a combination of oxamniquine ?.ZWINGENBERGER. All of them. Two females allo cated to the praziquantel group were exempted that at a certain moment the open random allo cation brings about a disproportional distribution of patients âmongst groups. F. E. 3¿ FELDMEIER. . even at low dosages. The patients were then rândomly allocâted to.29:305 3tr. excretion exceeded 300 per gram. J. Tlhese preliminary findings have not yet been clinically ilvestigated in northeastern BraáI. mansoni strains resistant to oxâmniquine exist32. Thus we have carried out â field trial at this endemicâl region in order to compare the efficacy of â half-dose combination on these two drugs âgâinst each one alone. A. U. Subjects with previous history of seizures were excluded ftom the trial. it has been successfu lly used in oxamniquine-resistant câses of schistosomiasis mânsonia e 20. reactions have been reported following its administrations 16 ¡6 37 47. They received therapy post-partum butwere excluded from the evâluauon. trop. J. 70 males and 23 females. approximately I g of stool salltple was examined by the merthiolate formol lMlf') concentrâtion technique6. whereas below this level fâìse-negative results are frequenta6.I POGGENSEE. Unfortunâtely it also became âpparent already at early stages of the eradi- The number of eggs per gram of fâeces prior to treâtment was calculated from five slides (equivalent to 210 câtion campaign in Brazil that S. taken 4 hours apârt. up exâminations performed on a single speci men obtai¡ed three. Only 20% were younger than 16 or older than 30 yeâ. Med. and there v. Brazil. mansoni3 r3 20 44.Emcact of oxamniqui¡e.one ofthe following treatment group: (a) oxamniquine 15 mg/kg in a sin gle dose. mg/kg. The Unequal number of patients within lhe three groups was due to the non-prefixed limitâtion in the âmount of cases entering the trial. . comprised a minimum of ten slides (corresponding to 420 mg of stool) per patient. ftom treâtment at the beginning of the study because of pregnancy. 198?.5 mg/kg plus praziquantel 20 Recentlyithas been suggested that the com bination of oxamniquine and praziquantel. Parasitological follow- Prâziquantelis a novel antihelminthic agent active against all schistosome species pathogenic to manr 26 ae âs well as a variety of other huma¡ tremâtode50 and cestode2T infections. 306 Statistical evaluation was performed accordingto Fisher's exact test for comparison ofrelative frequencies. Thfuty-two individuals vsere ¿reated with oxam niquine. lnst. whereas in 26Eo. six and twelve months posttreatment. J.i ESMERALDA.

* ** Twice 20 mg. 16 30 ys.J-A.9 -230 . 6 and 12 montbs after treâtmenb (for iegative stool sâmples þy Kâto-Kâtz but posiüive by MIF concentration. Bev. 29t6 20 ys. of the treated patients could be reexa mined three. positive cases ând eggs excreted pe¡gram of fâeces at different points of the follotr¡-up pe riod. and inclusively with the combinationr0 rs 2l. I56 EPG 132 . 6t. 2t (6tqol I I 5q.Oqo l5-25. < 16 2tsc 785ô 564.ESMERALDA Eñcacy of oxamDiquine. e.216 EPG EPG 176 EPG EPG 120 216 25V.iNOGUEIR'AQUEIIÙOZ.both d¡ugs in schlstosomiâsis mânsoni Ir. oxâmniquine. mansoni eggs per grâm orfaecesl Drug groups Dosages (mg/kg) 40+ 24 Orâmniquine 15 oxM & PzQ 'L5 + 20 Treâted câses Sex Mâle/female 32 16/8 25t7 21 ys.7c/. conJidence intervâl.93.ZWINGENBERGER. 24.) 2 3lSSat 8l2í7./.K. 12: 50 ys. four hours apalt. & FELDMEIEI¿.. 507.2 4 (14%) to - -25 94.POGGENSEEU:ALENCARJE-VALÐEGIIN-AS. an EPG of 5 wâs â36umed i¡ order . EPG ln non-cu¡ed câ6es Mohth Reductlon ofEPG - ra¡ge - rânge 5-45 39. 42.87c 22 (92C. PZQ EPG = number ofs.o calculate the reduction in ova excrctlotr¡ Foltow-up Controls Findinss Examined paüents* Dose Praziquantel ta (11L. R. Med. i. H. 225ô 12 54 ys- ys.l tr - 5-10 93. EÞG < EPG 100 300 EPG > 3OO EPG 1OO 328 455.' 48 87. 25V./o 2LVô Med¡ân 13? bùrden Limits** 100 .OSa - 99.81.97. Seventy-two percent.2 . 957.Inst. 10 .J-.9'lo t 99ô) 72. The cure râtes. six and twelve months after therâphy.5 . praziquântel ând a combi¡âtion of. Month EPG in non-cured Reduction ofEPG câses - range 20 ta3sal - ¡ange 46. 89% and 897. > 30 ys. 235.8 96. Median R ânge 22ys. 0 groups oxM & PzQ 26 t811êt 2 t 8q.ESULTS Ctinical tolerability to all three medications was uneventfull as no difference was noticed i¡ regard to the usual side-effects already reported in Brazil with praziquantel. Sáo Pauto. 449/.8qô Examined pâtients+ 8th Montb non-cu¡ed cases .29:305 311. lBq.) 24 3rd. Table II shows the number of examined pa tients. * ln brackets.r - r88 . failure to detect ova TABLE II paúsitotogicat findings 3. 198? TABLE I : pÌâziquantel Chârâcteris üics of the pâtients wìthin th e three drug groups ( OXM = oxâmniqume. troÞ. the Dercentage ofreexamined cases in ælatlon to Feâted Þatients *r In brackets ttìe perceniâge ofpositive cases in relation to reexamined pafients307 .7c.230 28V. lll Braziì. 62 ys.range rânge Reduction ofEPG EPG 30lg4Sot 6 (20Val 5 32.96. 22Va 6I7. respectively.5 3219L5.5% Examined patients* 12 30 (9450) 4 tlSqot 2A ßOS"t th.t ?6.

those negaCive ât the filstfollo\¡/-up buLpositive on subsequent examina crons edenoted byopencirctes.2V. however. and gEVo. 81. l iVa. The relative frequencies of parasitological cures did not differ statistically bet{¡een the groups. and the number of remaining positive câses was too small to allow statistical comparison of persis_ ting excretion of S. prâziq u antel ând â com bin â tion o l bo rhVALDEGUNAS. 87 Ea for oxamniquine. troD. mansoni. ESMERALDA. J./e¡ than in the tv/o remaining groups. oxamniquine and the combi_ nation respectively. Med. K.ETION IN INDTVTDUAL PATIENTS (po¡nts indrcatb the Epc ofeâch case. it has been disclosed that a low_ dose combination ofboth drugs is effective. 29:305 Bll. In our trial the post-treatment decrease of S.?7¿ in those patients in whom no 308 ference in the reduction of the mean numbers of eggs Fer grâm of faeces afteÌ heatment with praziquantel in compârison to oxamniquine has been reported in a much larger sized samplel?. DISCUSSION In those patients still excreting eggs after treatment. glEa for praziqu ntel. Drug goups Negâtive cases t S. tnst. MANSONT OVA EXCR. corresponding to these conrrol ìn tervâls were: 100Ea.rried out in Brazil 14 22 34.i F & FELDMETER Tl Eflicacv of oxamniquine. J.. 92Eø.96gù. 80Ea. quantüled)- Pmziquântel Oxâmniquine 26 6 ¿3 PZQ l8 4 8r. â statistically significant dif_ Our results confirm the similar efficâcy of praziquantel and oxamniquine \¡/hen used in conventional dosages for tleating S. In this connection.ZWINGENBERGER. considerable reductions in egg counts were observed.85ô complete pâ¡asitologÍcal cure was accomþli_ shed. A. They also did not differ A similat dosage to the one !¡¡e used in this trial has previously shown to be advantageous in a dose-hnding study conducted in Malawia3The children treated in this country had 2 to 4 times higher egg counts prior to treatment. cure rates of 81. dru gs in schis tosomiâsis m ansoni i¡ Blâzil. haematobium. In thât study.i NOGUEIR¿. Í'ith 6?. tg8? in the faeces. U. pOGGENSEE. Rev. mansoni ova excrelion and cure ¡âte seemed more favourable for the group treated with prazi quantel alone. J. Sáo pauto. as shown in Tat te III. TABLE III OverâU æsults of the pâlâsibotogicat exâminations by Kato-Kâtz ând MIF methods.97Ea). hor¡rever.. Taken into account the findings of the MIF concentration in addition to the re sults by Kâto Katz. It is visualized in Figure 1.plus 20 m g/k g praziq ua nT. as compared to the group treated with 10 mg/kg oxamniquine.b mg/kg oxamniquine plus 15 mglkg praziquantel. eUE'*OZ.el (98% vs. the initial egg count was slightly lov. * Onepatientilrthe oxâmntquine and one in the combination group was found posit¡ve by the MIr' concentration ontv. du¡ns the entùe 12 month follou/ Lrp. signiflcantly between the three groups. that the reincrease of egg ex cretion in non-cured Þâtients âppears to be stee_ per in those treated with oxamniquine than in those who received prâziquantel.6% of patients no longer excreting ova âfter the treatment and an average ¡eduction of egg counts of 88. ll 67 _6Vo 8t. E. Mediânsand gb¿l. as already demonst¡ated in double blind comparative trials ca.2qa and 62.8%. âccording to the Kato Katz method. A reincreâse in egg counts upon reexâmiúation six and twelvemonths aftertreatment wasnoted in two to three patients in eâch group in whom the counts had fallen to nought or 10 eggs per . and embraceing the whole twelve months ofparasitologicâl follow up. 86% for tlle combination. In addition. conñdence Iimits prior Lo bhenpy are indicated byhorizontal bars. mansoni i¡_ fection. and many were concomitanfly infected with S. FoÌtow up examina¿ions posiiive by MI¡' concenhation only are not Frg. the ¡eduction of ova excretion three months after therâpy was marginâlly los¡er using ?.85EÒ.. Six months after treatmenú lit e difference was appârent betvr'een the two dosage schemes (95Vo vs.62¿ were achieved wiôh praziquantel.t AI_ENCAR.

Fo¡taleza. J.4: 23 28. 29:305_311. the assessment of oxamniquine efücâcy by the quantitative oogram technique hâs been indicative ofpersistance ofegg ptoduc- Concluiu-se que os trés regimes terapêuticos. F.& SOUZA. J AiPOGGENSEE U. N..Aner. & SPINOLA. .oxamniquine (15 mg/kg) e praziquantel (40 mg/kg) empregadâs isoladamente. This finding was most pronounced on the 6th. Nâidu. R.¡SMERAIDA' Efücacy of oxâmniqume. It remains speculative whether this combination v¡ill prevent fl¡rther development of oxamniquine resistance.8-96.5Va collr a combinaçáo..Treatrnent of complicâted schistosomiasÍs man sonr v'ith oxamniquine. BLAGG. Stórzel.19?8.54:6 ?. . BERTI. variou de 93. Hyg.L. Med. NOGUEIRA QUEIIùOZ. Technical as- sistance wâs âlso frroyided by E. I): 538-541. de .curados.. Med.Susceptibility to chemotherapeutic agents of shâins of s. ACKNOWLEDGEMENTS The collaboration ofSUCAM held microsco In conclusion. P. alo praziquantel e ala P. L A new concenEation rechnique fo¡ iiemorìshation ofprotozoa and helminth eggs in f€ces. Hys. 1980. nas doses utilizadas. 1981.9 99. C. C. H. 81. Bento is greatly âppreciâted. Trib. A. DIá. as anâlogous cure rates and reductions of egg excretion in non-cured cases were achieved. P.Convuìsáo associadâ ao uso de oxâmniquì¡e. in two cases treâted with this drug the egg counts reached pre therapeutical levels. Romulo M. por via oral. (VeD€zu€la). 3l (Suppl. de J. S. Double blind clinicâr - 309 . J.. K. M¿d. in Brazil. no B¡asil. Rev. Rev. representando â ausência de ovos nas fezes em todos os con- troles durante o acompanhamento parasitoló BRANCHINI. Adusu. '7. mansoni strâihs to this drug but the possibility ofreinfec gico individuâlizado dos pacientes.-A. Actually.j DIAS. d¿ KHALAF. Amer. H. G. Med. a oxamniquine e â combinaçáo.ESUMO ÁNDREWS. t¡op.5 mg/kg) mais praziquantel r20 mg/kg.29:890'895. Conduziu-se um ensaio clínico Þara compa râr a eficácia de uma combinaçáo em baixas doses de oxamniquine (7. Drug Res. o praziquantel. 198? gram 3 months post therapy. Hyg.. - EnEayo Os medicâmentos foram administrados. tion or relapse cannot be ruled out either. de S. Z.. MANSOUR. J E-: VALDEGUN-A. a single dose administration mg/kg or praziquantel40 mg/ kg or a half-dose combination of both drugs pro ved to be similarly effective in schistosomiasis mansoni in Brâzil.& DEBERALDINI. dáo resultados similâ- tion four months on after treatment12. teEpéutìco conpraziquanttel en casosde schistosomiasis mânsoni resistenües al oxamniquine. BASSILY. do Nascimento ând Maria A. J. ïqeber-Adusu and K. & SCHMIDT DOMMERQUE.21ø e 67.S. J. 1981. E. Finally it should be emphanot to be extrapolated to large scale therapy. a 91 pâcientes. respectivamente. PEDRO. Eansoni isolated hom tùeated ând unheated pa tients. lot 221 -223.ZWNGENBERGER. foram de Al. R. Med. troÞ. Os Índices de cuta alcançâdos. C. t¡oÞ. sized that these are only preliminary results control in Brazil.5-979a com a oxamniquine e ?6.6Ea com. Prof. J. A reduçáo do número de ovos eliminado por grama de fezes nos casos náo. N. Z7: R. de S. J. E. 1955.8% com o praziquantel.AVo. res e satisfâtó¡ios no tratamento da esquistossomose mânsônica náo complicada. 32. P. aleatoriamente. L & WÀTTEN. This could be due to a diminished susceptibility of S. SCHLOEGEL.A summary ofthe efñcacy ofprâziquânt€l âgâinst schis iosome in animal experiments and notes on lts mode of action. W-. KATZ. mitidos no ensaio foram reexaminados segundo os métodos de Kato-Katz (dez lâminas) e MIF (um grâma de fezes). J. Eficácia ala oxamniquine. Inst.. Soc. L. 197 6. aroú... ned. E. ARAUJO. M. HIGASHI. S-i FARID. Relaüo de um caso. amer. In regâ¡d to this. month after treatmentin the oxamniquine group. R. which could turn into a serious hazard for schistosomiasis ofoxamniquine 15 pists.LENCAR. com ambas as drogas . L. Univer sidade Federal do Ceârá.S J. Seis e doze meses depois do tratâmento 89% dos ad- BINA. combinaçáo ile ambas as drogas na esquistossomose mansônica no Brasil. .- 1284 1286.. gave valuable advises.. G. N. & FELDMEIER. treF. M. br¿s. Sáo Pãüto. pmziquanüel ând â combinâlion of both drugs in schistosomias$ mânson¡ F. no tratamento da es quistossomose mansônica em uma área endêmica do nordeste brasileiro.

Z.B. 27: 132 142.i 10.TZ. 19?g.ID. t9B2 tleat¡neni of trial comparing prâziquantet v/¡bh oxamniquine Ín the quine in the b¡eâtment ofmansoni schistosomiâsis. _ A associåção de oxâmmqu¡ne e ptaziquantet no tratamen¿o dâ esqujstossomose mansónica.ExpeÍêncta com quimioærapra em granae escala no controle dâ esquistossomose no Brasjl. s. A. Hys. lrÌas. & CARBONI. EMANUEL. MOREI RA. N. G.Associaçao de drogâs no hatâmento alâ esquisto6_ somosemansoni experimentât. R¿v. _ Comparaçáo enûe prâzr quantel e oxâmniqulDe no Þatâmento atâ esqu¡stossomo se rnansoni..31:601 603. . de S. S..Efeitos colaterais e eficáciâ da associaçâo oxamniquinelpraziquantel no hâtamento da infecçáo humanâ pelo Schistosoma Eånso¡i.i VILELA.Inst. mansoni to schistosomi cidal âgents. ner.. tmp.ugs in schistosomiâsis mansoni . trcp. C.. I<. E. paulo. 1980. & LUCAS. ?6: 652 689. Rev.& WATTEN. S¿ú110.A QUEIR. _ To. 30. Soc. Z. TROpICAL.. pOGGENSEE. V.. L.t. R. H. _ ptaziquâ¡ìtel a new bload spectrum antisahistosomât agent. res. em áteâ enatèmlca. prâz¡quântel and a combinat¡on of both d. _ Neuro- HIRSCI¡.EID. Meat.296. p. Med. pâuto. 1983. Eev.scHENcI<ING. CAMPOS. Ihst. ment of patie nts with schistosomiâsis mânsoni: a double prâz¡quantel. C. CIR Batieùo Editores. T'. n¡st.i SAEZ-ALQUEZAR.ASILEIRA DE MEDICINA TR. S. V.Á. R. LACET. D.i TCIÌ. 1985). Rev. R. PEDI¿O. E.å. 26. ao hycant¡onê e oxâmnlquine em doentes -Resistenciâ com esquls iossomose iolm a clinicâ hepatintestinal. S. A. 16: 90 93. 19. rMesa-ædondano XXI CONGRES SO DA SOCIEDADE BR. 18. ESMERAI. M.180.omose man sõn¡câ..OITBERG. 1985. _ pmziquantet in the t¡eâtment L_ C. OLÌVEIRII. M.. J. Paulo. E.Iì-i PINTO. P. t98?.l9: 24? 249. ¡. 5t. Med. de S.. F'R.. M A. troD. R.i SHIROIiÍA. Z?: 328.AKERIAN. 24: r80-lB?. (Bãs€t). E. ateC _Tæatblind clinicât t¡iat compadng gazlquantel with oxamni quine.OPICAL.. Rev.t R'IGO.q.A avâtiaçáo berâpêuüica da oxÊmniqu¡ne nâ esquistossomose mâ¡soni humanâ peto métocto do oograma por blópsiâ de mucosâ retat.. GUIMARÃES. V. KATZ. Inst. G¡¿YSCHEI(. t984. Med. J. S.. C. -Tleatment ofhepa bosplenic schistoso miasis mamoni with praziquantel_ D¡us:Res. È. L.. J. São pauto. Sao pau lo.& PRATA. nêv. & PRATA.DA. s. p. in Brazfl. M.D¡ BRASILEIRA DE MEDICIN-ê. Med. & ScllULzE. P. I-I BASSiLY. C. HIGASHI. M. 19Bl of the hepatosplenic form of schistosorniasis mansoni. acta troÞ. LEVAI. fns¿. A. M.. GR.j NEVES. DOMINGUES.22: {0 51. C. Zt. DIAS. L. ú¡op. SHIKANAI-YASUDA.. & ALMEIDA.): 5?. t9?8. hst. de J.. F. A. da CUNHA. V. A. ¡nst. U_iALENCAR.. R€v. K. Paulo.24: 88 94. Pâulo). PEDRO. H. _ AssocÍaçäo ale qùine e prâzÌquantel.. N. M.3l: 558 565. Drùs B€s. 1982. as comparect to some other schistosomicides.. Trâns. \7... Use of pråziquântel -mansoni previousty in patients with schistoso mÞsrs ileâted with oxamniquine ând/ or hycanthone: ¡esistance of S. 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