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Spatial Tissue Mapping on Joint Biopsies from Arthritis Patients

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(1)kth royal institute of technology. Doctoral Thesis in Biotechnology. Spatial Tissue Mapping on Joint Biopsies from Arthritis Patients KONSTANTIN CARLBERG. Stockholm, Sweden 2021.

(2) Spatial Tissue Mapping on Joint Biopsies from Arthritis Patients KONSTANTIN CARLBERG. Academic Dissertation which, with due permission of the KTH Royal Institute of Technology, is submitted for public defence for the Degree of Doctor of Philosophy on Friday 16th April 2021, at 10:00 AM in Air and Fire, Tomtebodavägen 23A, Solna. Doctoral Thesis in Biotechnology KTH Royal Institute of Technology Stockholm, Sweden 2021.

(3) © Konstantin Carlberg TRITA-CBU-FOU-2021:12 ISBN 978-91-7873-818-2 Printed by: Universitetsservice US-AB, Sweden 2021.

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(281) @BOC@NFDI<I?AGPD?N GDF@AJMDINO<I>@N<GDQ<<I?O@<MN%JR@Q@M

(282) OC@HJNOR@GG FIJRIJAOC@=J?TlN?@A@IN@NTNO@HNDN OC@DHHPI@NTNO@H

(283) RCD>CC<N!%%+<I?'+!->JHKJI@ION    1C@DII<O@DHHPI@NTNO@HKMJQD?@NDHHPIDOTOC<ODN@NO<=GDNC@?<O=DMOC<I??J@NIJO>C<IB@JQ@M OC@JMB<IDNHlNGDA@ODH@&II<O@DHHPI@M@NKJIN@N<M@DHH@?D<O@<I?IJI NK@>DAD><I?KMJQD?@IJ DHHPIJGJBD><G H@HJMT JIQ@MN@GT

(284)  <?<KODQ@ DHHPI@ M@NKJIN@N <M@ K<OCJB@I  JM <IODB@I NK@>DAD>

(285)  C<Q@ < G<B ODH@ =@OR@@I @SKJNPM@ <I? M@NKJIN@

(286)  <I? G@<? OJ <>LPDM@? DHHPIJGJBD><G H@HJMT1C@>@GGNJAOC@DHHPI@NTNO@H<M@FIJRI<N#,"&0+*  1C@ H@>C<IDNHN <I? >@GG OTK@N DIQJGQ@? DI OC@ DII<O@ <I? <?<KODQ@ DHHPI@ M@NKJIN@N ?DAA@M

(287)  <GOCJPBCOC@M@<M@NJH@GDIFN=@OR@@IOC@ORJ1C@HJNO>JHHJIG@PFJ>TO@NDIOC@=GJJ?<M@ I@POMJKCDGN

(288) RCD>C<M@JAO@IOC@ADMNO>@GGOTK@OJ<MMDQ@<O<NDO@JADIA@>ODJI  +@POMJKCDGN<M@ CDBCGTHJ=DG@<I?NCJMOGDQ@?

(289) <I?KMDH<MDGT<>OOJ>JIOMJGDIA@>ODJIN=T@IBPGADIB<I?GTNDIBOC@ . .

(290)    

(291) 

(292)  K<OCJB@IDI<KMJ>@NN><GG@?' &0+&*!* N@@ADBPM@ 2IAJMOPI<O@GT

(293) IJO<GGK<OCJB@IN><I=@ ?@NOMJT@?OCMJPBCKC<BJ>TOJNDN1C@M@AJM@

(294) OC@DHHPI@NTNO@H<GNJM@GD@NJIJOC@M>@GGOTK@NOJ ?@A@I?<B<DINO<OO<>FN GJN@GTM@G<O@?OJI@POMJKCDGN<M@@JNDIJKCDGN RCD>C<GNJ<>OKMDH<MDGTQD< KC<BJ>TOJNDN <I?=<NJKCDGN

(295) =JOCJARCD>C<M@<NNJ>D<O@?RDOC<GG@MBD@N<I?<NOCH<!@I?MDOD> >@GGN ! <I?H<>MJKC<B@N<M@KC<BJ>TO@NOJJ

(296) =POOC@T><I<GNJ<>O<N<IODB@IKM@N@IODIB>@GGN - AJM1>@GGN

(297) H@<IDIBOC<OOC@TH@?D<O@=@OR@@IOC@DII<O@<I?<?<KODQ@DHHPI@M@NKJIN@N  +<OPM<GFDGG@M +( >@GGN<M@<IJOC@M>MP>D<G>@GGOTK@DIOC@DII<O@DHHPI@NTNO@HOC@DMMJG@DNOJ ?@NOMJTC<U<M?JPNDI?DB@IJPN>@GGNNP>C<N><I>@M>@GGNJMQDMPNDIA@>O@?>@GGN  ?<KODQ@DHHPI@M@NKJIN@N<M@H@?D<O@?=T<IODB@IKM@N@IO<ODJIJI*% >G<NN&<I?&&NPMA<>@ KMJO@DIN

(298) RCD>CG@<?NOJOC@DMM@>JBIDODJI=TOC@1>@GGM@>@KOJM 1 / <I?NP=N@LP@IOGTOJOC@ KMJ?P>ODJIJA<IOD=J?D@N Innate immune responses. Adaptive immune responses Antigen presentation. Neutrophil. B cell Pathogen. T cell. Cytokines or cytotoxins. Phagocytosis. Memory B cell. T and B cell activation. Plasma cell Natural killer cell. Infected cell. Dendritic cell Antibodies. Induced apoptosis.  )7;>:74732=D3@D73E=4B6313::BG>3A/<2;316/<7A;A=4/1B7=<1=<<31B32B=B637<</B3/<2/2/>B7D3 7;;C<3AGAB3;A6=E7<523<2@7B7113::A/A=<3=4B63:7<9A03BE33<B637<</B3/<2/2/>B7D37;;C<3@3A>=<A3A. .  1C@1GTHKCJ>TO@N 1>@GGN <M@DHKJMO<IODIH@?D<ODIB<?<KODQ@DHHPI@M@NKJIN@N1>@GGN?@MDQ@ AMJHC@H<OJKJD@OD>NO@H>@GGNAMJHOC@=JI@H<MMJR<I?HDBM<O@OJOC@OCTHPNOJH<OPM@<I? ?@Q@GJKDHHPI@OJG@M<I>@OJN@GA <IODB@IN%@GK@M1>@GGN<M@<NP=N@OJA1>@GGNOC<O<M@<>ODQ<O@? =T - N QD< >JNODHPG<OJMT M@>JBIDODJI &I OCDN KMJ>@NN

(299)  OC@ >GPNO@M ?DAA@M@IOD<ODJI ! NPMA<>@ KMJO@DIJAOC@C@GK@M1>@GGM@>JBIDU@N<K@KOD?@<IODB@IKM@N@IO@?=T*% >G<NN&&KMJO@DINJI - N<I?OC@IA<>DGDO<O@NOC@M@>MPDOH@IOJAJOC@M>@GGOTK@NQD<>TOJFDI@NDBI<GDIB TOJOJSD>1 >@GGNJIOC@JOC@MC<I?<M@<>ODQ<O@?=T>JNODHPG<OJMTM@>JBIDODJIOCMJPBC !

(300) RCD>CM@>JBIDU@N K@KOD?@NKM@N@IO@?=T*% >G<NN&KMJO@DIN<I?KMJ?P>@N>TOJOJSDINOC<O><I?@NOMJT>@GGN  1C@>@GGN<M@<IJOC@MDHKJMO<IO>JHKJI@IOJAOC@<?<KODQ@DHHPI@NTNO@H>@GGN><I<>O<N - N=PO><I<GNJM@>JBIDU@<IODB@INPNDIBDHHPIJBGJ=PGDIN &BN ,I>@<I<IODB@IDNM@>JBIDU@? . .

(301)    

(302) 

(303)  =T < 1 >@GG

(304)  OC@ 1 >@GGN <>ODQ<O@ OC@  >@GGN

(305)  RCD>C ?DAA@M@IOD<O@ DIOJ KG<NH< >@GGN <I? M@G@<N@ <IOD=J?D@N RCD>C<M@=<ND><GGTN@>M@O@?&BN 1C@<IOD=J?D@NDIOPMI=DI?OJOC@DMO<MB@ON

(306) G@<?DIB OJM@>MPDOH@IOJAKC<BJ>TO@NOC<O?@NOMJTOC@DIA@>ODQ@<B@ION0JH@>@GGN=@>JH@H@HJMT >@GGNOC<O>JIA@MGJIB O@MH<?<KODQ@DHHPIDOT

(307) KMJO@>ODIBOC@CJNOAMJHNDHDG<MDIA@>ODJINDIOC@ APOPM@ .   /22/254/4/8*$53. 1C@ G<O@ 3' >@IOPMT KCTND>D<I -<PG "CMGD>C

(308)  RCJ >JI?P>O@? @<MGT DHHPIDU<ODJI @SK@MDH@ION

(309)  M@E@>O@?OC@D?@<OC<O<IJMB<IDNH>JPG??@Q@GJKDHHPI@M@NKJIN@N<B<DINODON@GA%@O@MH@?OCDN KMDI>DKG@ &))&),+&+&/!,*%JR@Q@M

(310) DODNIJRRD?@GTFIJRIOC<ODHHPI@<>ODQ<ODJI><IJ>>PM @Q@IRC@IIJK<OCJB@IN

(311) <GG@MB@IN

(312) JM><I>@M>@GGN<M@KM@N@IODIOC@CJNO1CDNNO<O@DNM@A@MM@?OJ <N<POJDHHPIDOT<I?DN>C<M<>O@MDU@?=T<IOD=J?D@NO<MB@ODIBN@GA <IODB@IN

(313) RCD>C><I@Q@IOP<GGT G@<?OJODNNP@?<H<B@  1CDNOTKD><GGTJ>>PMNOCMJPBCGJNNJADHHPIJGJBD><GOJG@M<I>@OJR<M?N N@GA KMJO@DIN1C@H@>C<IDNHNM@NKJIND=G@AJMOCDNJPO>JH@<M@G<MB@GTPIFIJRI

(314) <GOCJPBCDOC<N =@@I?@HJINOM<O@?OC<O<POJDHHPIDOT><I=@OMDBB@M@?=T>@MO<DI@IQDMJIH@IO<GJMB@I@OD>A<>OJMN  3 /+!%+!&%!*+ ),#,)-!-#!*+ /'+!&%4 )#% . )!(#&(&('.  1C@@OTHJGJBTJA/C@PH<OJD?<MOCMDODN / NO@HNAMJHOC@$M@@FRJM?N r~wq

(315) H@<IDIBjAGJRk JMj>PMM@IOk

(316) <I?zvzyxAJMjEJDIOk1C@N@<M@>JH=DI@?RDOCOC@NPAADS@N JD?AJMjM@N@H=GDIBk

(317)  <I? DODNAJMj<AA@>ODIBk

(318) BDQDIB<H@<IDIBJAjM@N@H=GDIB?@AGPSDJI

(319) <AA@>ODIBEJDIONk1C@N@RJM?N ?@N>MD=@OC@NTHKOJHNJAJIBJDIBDIAG<HH<ODJIOC@M@A@M@I>@OJAGJRDIEJDIONH<T=@DI>GP?@? =@><PN@<>C<M<>O@MDNOD>NTHKOJHJA/DN@?@H<DIOC@EJDION   .  *"(./3*.()&5-"4/*%"24)2*4*3. /C@PH<OJD? <MOCMDODN DN < NGJRGT KMJBM@NNDIB <POJDHHPI@ ?DN@<N@ RCJN@ @<MGT NTHKOJHN <M@ OTKD><GGTHDG?OC@TDI>GP?@R<MHOC

(320) NR@GGDIB

(321) <I?K<DIDIOC@EJDION

(322) K<MOD>PG<MGTDIOC@RMDNON<I? C<I?N1CDNBM<?P<GGTG@<?NOJ>CMJID>DIAG<HH<ODJIJAOC@EJDION<AA@>ODIBOC@PI?@MGTDIB=JI@ <I?><MODG<B@

(323) RDOCDI>M@<NDIBGTN@Q@M@NTHKOJHNDI>GP?DIB=JI@@MJNDJI<I??DN<=DGDOTM@<>C@?DA PIOM@<O@?  &IO@MI<ODJI<GGT

(324) OC@H@<IKJDIOKM@Q<G@I>@JA/R<N=@OR@@I<I? DONK@MDJ?KM@Q<G@I>@=@OR@@I<I?R<N    I@RK<M<?DBHAJMOC@?D<BIJNDNJA/R<N@NO<=GDNC@?DIRC@I<>JGG<=JM<ODQ@DIDOD<ODQ@ @NO<=GDNC@? =T OC@ H@MD><I JGG@B@ JA /C@PH<OJGJBT <I? OC@ "PMJK@<I )@<BP@ B<DINO /C@PH<ODNH  /"2)/  DIOMJ?P>@? I@R >G<NNDAD><ODJI >MDO@MD< PNDIB OC@ !@GKCD H@OCJ?

(325)  2I?@M OCDN <KKMJ<>C

(326)  ?D<BIJNDN DN K@MAJMH@? =T N>JMDIB A@<OPM@N NP>C <N EJDIO DIQJGQ@H@IO

(327)  N@MJGJBT

(328)  <>PO@ KC<N@ M@<>O<ION

(329)  <I? ?PM<ODJI JA NTHKOJHN 1C@ NTNO@H OCPN KPON R@DBCO JI A@<OPM@NJ=N@MQ@??PMDIBOC@@<MGTNO<B@NJA?DN@<N@OC<O<M@<NNJ>D<O@?RDOCK@MNDNO@IO<I?@MJNDQ@ NTHKOJHNM<OC@MOC<IAJ>PNJIDONG<O@ NO<B@A@<OPM@N  . '$$+/'(,$3'.#2314"341$#".,,4-(" 3(.-3$"'-(04$6'$1$/ -$+2.%$7/$132 -26$104$23(.-- (1$2(-2$5$1 +1.4-#2%3$1$ "'1.4-# % "(+(3 3.1"1$ 3$2 -.-8,(9$#24,, 1($2.%3'$$7/$132<%.1$" 232%1.,3'$/1$5(.421.4-#(-"+4#(-&)4#&$,$-32%3$12$5$1 +1.4-#23'$ -26$12".-5$1&$3.6 1#22.,$*(-#.%".-2$-242.-'.63.' -#+$ 3./(". . .

(330)    

(331) 

(332)  NDHDG<M<KKMJ<>CR<N<?JKO@?DIOC@@<MGD@M />G<NNDAD><ODJI>MDO@MD<

(333) RCD>CAJ>PN@?JI OC@KM@N@I>@JA<MOCMDODN<AA@>ODIBC<I?EJDION<I?NTHH@OMD><GEJDIODIQJGQ@H@IO

(334) RCD>C<M@<GNJ A@<OPM@N<OQ@MT@<MGTNO<B@NJA/     /HPNO=@?DNODIBPDNC@?AMJHJOC@M>JI?DODJIN<NNJ>D<O@?RDOCEJDIOK<DI

(335) DI>GP?DIBJNO@J<MOCMDODN ,

(336)  NTNO@HD> GPKPN @MTOC@H<OJNPN 0)"

(337)  AD=MJHT<GBD< #*  <I? NKJI?TGJ<MOCMDODN 0K  OJ H<SDHDU@OC@=@I@ADOJAO<MB@O@?DIO@MQ@IODJIN

(338) RCD>C>PMM@IOGTM@GTH<DIGTJIOC@PN@JA!DN@<N@ *J?DATDIB <IOD /C@PH<OD> ?MPBN !*/!N  1C@ KMJ>@NN JA ?DNODIBPDNCDIB / AMJH JOC@M ?DN@<N@NOC<O><PN@NDHDG<MNTHKOJHNDN><GG@?!)%+!#!%&*!*  @AJM@?DBBDIBDIOJOCDN >JI>@KO

(339)  DO NCJPG? =@ IJO@? OC<O K@JKG@ ><I =@ <AA@>O@? =T N@Q@M<G <POJDHHPI@ ?DN@<N@N NDHPGO<I@JPNGT

(340)  APMOC@M >JHKGD><ODIB ?D<BIJNDN 1C@M@AJM@

(341)  MPGDIB JPO JOC@M ?DNJM?@MN M@LPDM@N MDBJMJPN@S<HDI<ODJIN

(342) RCD>CH<TO<F@PKOJN@Q@M<GR@@FN .   2&"4-&.4/')&5-"4/*%"24)2*4*3. &A / DN NPNK@>O@?

(343)  OM@<OH@IO OTKD><GGT PNDIB !*/!N <N H@IODJI@? <=JQ@  DN DIDOD<O@? M@HDNNDJI<AO@M!*/!OM@<OH@IOH<T=@O<F@I<N>JIADMH<ODJIJAOC@/?D<BIJNDN!*/!N <M@?@NDBI@?OJNGJROC@KMJBM@NNDJIJA/1M@<OH@IOM@BDH@NOTKD><GGT=@BDIRDOC<NTIOC@OD> !*/! NP>C <N *@OCJOM@S<O@ 1CDN H<T =@ AJGGJR@? =T OM@<OH@IO RDOC =DJGJBD> !*/!N O<MB@ODIBK<OCR<TNJAOC@>TOJFDI@>JHK<MOH@IONNP>C<N1+# q

(344) DIO@MG@PFDIM@>@KOJMN &)

(345) JM NPMA<>@<IODB@INNP>C<N !OJDI?P>@>@GG?@KG@ODJI    &A!*/!OM@<OH@IOG@<?NOJM@HDNNDJIJMJKODH<G>JIOMJG

(346) DODNJAO@I?JN@?<OH<DIO@I<I>@G@Q@GN !DN>JIODIPDIB!*/!OM@<OH@IOH<TM@NPH@OC@?DN@<N@KMJBM@NNDJI

(347) <I?OC@M@DNIJBP<M<IO@@ OC<O?DN@<N@>JIOMJGRDGG=@M@NOJM@?PKJIM@NPHKODJI  / ><I <GNJ =@ OM@<O@? PNDIB IJINO@MJD?<G <IOD DIAG<HH<OJMT ?MPBN +0&!N

(348)  RCD>C OM@<O OC@ NTHKOJHN ><PN@? =T DIAG<HH<ODJI =PO IJO OC@ PI?@MGTDIB ?DN@<N@

(349)  <I?JM RDOC NO@MJD?N OC<O ?<HK@I OC@ DHHPI@ M@NKJIN@ =PO ?J IJO NGJR OC@ KMJBM@NNDJI JA OC@ ?DN@<N@ 1M@<OH@IO RDOC +0&!NJMBGP>J>JMOD>JD?NH<T=@C<GO@?JI>@M@HDNNDJIJMJKODH<G>JIOMJGDN<>CD@Q@?  1C@<B@IONH@IODJI@?<=JQ@H<T<GG@QD<O@OC@NTHKOJHNJAOC@?DN@<N@<I?C<GODONKMJBM@NNDJI

(350)  <GGJRDIBDOOJ=@>JIOMJGG@?%JR@Q@M

(351) IJ>PM@AJMOC@?DN@<N@@SDNON<OKM@N@IO

(352) <I? JA K<OD@ION RDOC MC@PH<OJD? <MOCMDODN @SCD=DO IJ M@NKJIN@ OJ <IT =DJGJBD><G OC@M<KD@N 1C@M@AJM@

(353)  OM@<ODIB/DHKJN@NCPB@>JNONJIC@<GOC><M@NTNO@HNDI0R@?@I<GJI@

(354) DO>JNO0"(=DGGDJIDI <>>JM?DIBOJOC@0R@?DNCDINODOPO@AJMC@<GOC@>JIJHT   .   2/(2&33*/./')&5-"4/*%"24)2*4*3. $@I@OD> KM@?DNKJNDODJIN OJR<M?N OC@ ?@Q@GJKH@IO JA / C<Q@ =@@I J=N@MQ@? DI A<HDGT NOP?D@N

(355)  RC@M@OC@>GJN@NOM@G<ODQ@NJA/K<OD@IONR@M@AJPI?OJ=@<OOC@BM@<O@NOMDNFJA?@Q@GJKDIBOC@ ?DN@<N@ OC@HN@GQ@N 0@Q@M<G B@I@OD> MDNF A<>OJMN C<Q@ =@@I NPBB@NO@?

(356)  IJO<=GT OC@ %PH<I )@PFJ>TO@IODB@I %) NC<M@?@KDOJK@ 0" <GG@G@N

(357) RCD>C@I>J?@>@GGNPMA<>@KMJO@DINRDOC NOMP>OPM<GNDHDG<MDOD@NDIOC@K@KOD?@ =DI?DIBBMJJQ@ K<MOD>PG<MGTDI%) !/

(358) <N@S@HKGDAD@? =TOC@<GG@G@%) !/   JGG@>ODQ@GT

(359) OC@0"<GG@G@NH<T@SKG<DI<NHP>C<NJAOC@ B@I@OD> MDNF JA /   "IQDMJIH@IO<G A<>OJMN <M@ <GNJ DHKJMO<IO OJ=<>>J NHJF@ @SKJNPM@

(360)  J=@NDOT

(361) HD>MJJMB<IDNHN DIA@>ODIBJI@NNP>C<NOC@=<>O@MD<><PNDIBK@MDJ?JIODODN<NR@GG<NOC@ HD>MJ=D<G>JHHPIDOT>JHKJNDODJI <I?@Q@IDIEPMTH<T>JIOMD=PO@OJOC@?@Q@GJKH@IOJA/ . .

(362)    

(363) 

(364)  1C@@ODJGJBTJA/DNPIFIJRI

(365) =PONJH@K<OCJKCTNDJGJBD><GH@>C<IDNHNC<Q@=@@ID?@IODAD@? <I? ><O@BJMDU@?

(366)  DI>GP?DIB IJI NK@>DAD> DIAG<HH<ODJI

(367)  1 >@GG <>ODQ<ODJI

(368)  <I? ADI<GGT >CMJID> DIAG<HH<ODJIRDOCODNNP@DIEPMTM@NPGODIBAMJHOC@<>ODQDOTJAOC@>TOJFDI@N&) 

(369) 1+# q<I?&)   &OC<N=@@INPBB@NO@?OC<OOC@JIN@OJA/H<T=@GDIF@?OJKJNDODQ@A@@?=<>FH@>C<IDNHNAJM >@MO<DIN@GA <IODB@INOC<O><IJQ@MRC@GHI@B<ODQ@A@@?=<>FGJJKNOC<OIJMH<GGTH<DIO<DIOJG@M<I>@ "S<HKG@NDI>GP?@OC@=DI?DIBJAMC@PH<OJD?A<>OJMN /#N OJ#>M@BDJINJA&B$N<I?OC<OJA<IOD >DOMPGGDI<O@? KMJO@DI <IOD=J?D@N  -N  OJ >DOMPGGDI<O@? KMJO@DIN 1C@ ?D<BIJNOD> NK@>DAD>DOT JA OC@N@<POJ<IOD=J?D@NAJM/DN<MJPI?K<OD@ION@SKM@NNDIBOC@H<M@><GG@?N@MJKJNDODQ@/ K<OD@ION<I?<>>JPIOAJMOC@H<EJMDOTJA/><N@N1C@<POJ<IODB@INOJRCD>COC@<POJ<IOD=J?D@N =DI?A<GGDIOJ?DAA@M@IOBMJPKN

(370) <I?NJH@<M@<NNJ>D<O@?RDOCEJDIONJMK@MDKC@M<G<M@<NPOJ<IODB@I AJMH<ODJI ><I J>>PM RC@I OC@ DHHPI@ NTNO@H @I>JPIO@MN AJM@DBI <IODB@IN RDOC CPH<I CJHJGJBP@N =PO DI / DO N@@HN OJ =@ DIDOD<O@? =T KJNO OM<ING<ODJI<GGT <GO@M@? KMJO@DIN NP>C <N >DOMPGGDI<O@?AD=MDIJB@I<I?QDH@IODI    1C@ DIDOD<ODJI JA <POJDHHPIDOT DN AJGGJR@? <AO@M NJH@ T@<MN =T DI>M@<N@? DIAG<HH<ODJI ?P@ OJ NF@R@?<IODB@IKM@N@IO<ODJI<I?CTK@MM@<>ODQDOT,I>@OC@<=IJMH<GDHHPI@M@NKJIN@C<N=@>JH@ @NO<=GDNC@?

(371) KG<NH<>@GGNKMJ?P>@MC@PH<OJD?A<>OJMN JAO@I&B* <I? -N JAO@I&B$ DIG<MB@ <HJPION1C@N@<>ODQ<O@H<>MJKC<B@NQD<>JHKG@H@IO=DI?DIBJAOC@#>M@>@KOJM&IOCDNKMJ>@NN

(372)  H<>MJKC<B@N <I? ?@I?MDOD> >@GGN API>ODJI <N <IODB@I KM@N@IODIB >@GGN

(373)  RCDG@ <>ODQ<O@? ! <I? ! 1 >@GGN @IO@M OC@ DIAG<H@? <M@< <I? AJMH HD>MJN>JKD> <BBM@B<O@N 1C@ @INPDIB >CMJID> DIAG<HH<ODJI DN >C<M<>O@MDU@? =T @SO@INDQ@ I@JQ<N>PG<MDU<ODJI <I? ODNNP@ ?<H<B@ ?P@ OJ OC@ <>ODQDOT JA >TOJFDI@N

(374)  >C@HJFDI@N

(375)  <I? H<OMDS H@O<GGJKMJO@DI<N@N 0DBI<GDIB QD< /+() <I? /+( JA OC@ 1+# q NPK@MA<HDGT  AMJH <>ODQ<O@? NTIJQDJ>TO@N DI OC@ EJDIO NK<>@ @Q@IOP<GGT OMDBB@MNJNO@J>G<NOKMJ?P>ODJI

(376) RCD>C?@BM<?@N=JI@1CDNOTKD><GGTG@<Q@NOC@K<OD@IORC@@G>C<DM =JPI?4CDG@<?Q<I>@NDIOC@M<KD@N<I??D<BIJNDNC<Q@H<?@DOQ@MTM<M@AJMOC@?DN@<N@OJKMJBM@NN OCDNA<M

(377) OC@M@DNNODGG<I@@?AJM=@OO@MR<TNJA?@O@>ODIBOC@?DN@<N@DIOC@@<MGTNO<B@NJADONJIN@O

(378)  RC@IK<OD@ION@SCD=DO@G@Q<O@?DIAG<HH<ODJI=POIJJOC@MNTHKOJHN .   $4/0*$,9-0)/*%3425$452&3. ">OJKD>GTHKCJD?NOMP>OPM@N ")0

(379) RCD>C<M@<GNJFIJRI<N1@MOD<MT)THKCJD?,MB<IN 1),N

(380)  <M@>GDID><GA@<OPM@N>JHHJIGTJ=N@MQ@?DI?DN@<N@NNP>C<N><I>@MN

(381) <POJDHHPI@?DN@<N@N

(382) <I? DIA@>ODJIN

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