Bisoprolol reverses down-regulation of potassium channel proteins in ventricular tissues of rabbits with heart failure

Bisoprolol reverses down-regulation of potassium channel proteins in ventricular tissues of rabbits with heart failure

+#3 +PVSOBMPG#JPNFEJDBM3FTFBSDI喏喏   3FTFBSDI1BQFS I U U Q  F M T F W J F S D P N  X QT  G JOE  KPVS OB MEFTDS JQU JPODXT@ ...

164KB Sizes 0 Downloads 34 Views

+#3 +PVSOBMPG#JPNFEJDBM3FTFBSDI喏喏   3FTFBSDI1BQFS

I U U Q  F M T F W J F S D P N  X QT  G JOE  KPVS OB MEFTDS JQU JPODXT@ IPNFEFTDSJQUJPOEFTDSJQUJPO

#JTPQSPMPMSFWFSTFTEPXO-SFHVMBUJPOPGQPUBTTJVNDIBOOFMQSPUFJOT JOWFOUSJDVMBSUJTTVFTPGSBCCJUTXJUIIFBSUGBJMVSFƿ 9J-JB C D E 5JOH[IPOH8BOHB C D ,F)BOB C D 9JBP[IFO;IVPB C D 2VO-VB C D "JRVO.BB C D B

%FQBSUNFOUPG$BSEJPWBTDVMBS.FEJDJOF UIF'JSTU"GGJMJBUFE)PTQJUBMPG.FEJDBM4DIPPM 9J’BO+JBPUPOH6OJWFSTJUZ 9J’BO  4IBBOYJ $IJOB C ,FZ-BCPSBUPSZPG.PMFDVMBS$BSEJPMPHZPG4IBBOYJ1SPWJODF 9J’BO 4IBBOYJ $IJOB $ ,FZ-BCPSBUPSZPG&OWJSPONFOUBOE(FOFT3FMBUFEUP%JTFBTFT 9J’BO+JBPUPOH6OJWFSTJUZ 9J’BO 4IBBOYJ $IJOB E %FQBSUNFOUPG$BSEJPWBTDVMBS.FEJDJOF UIF4FDPOE"GGJMJBUFE)PTQJUBMPG.FEJDBM4DIPPM /JOHYJB.FEJDBM6OJWFSTJUZ  :JODIVBO /JOHYJB)VJ"VUPOPNPVT3FHJPO $IJOB 3FDFJWFE.BSDI 3FWJTFE"QSJM "DDFQUFE.BZ

"CTUSBDU 3FNPEFMJOHPGJPODIBOOFMTJTBOJNQPSUBOUNFDIBOJTNPGBSSIZUINJBJOEVDFECZIFBSUGBJMVSF )' 8FJOWFTUJHBUFEUIFFYQSFTTJPOPGQPUBTTJVNDIBOOFMFODPEJOHHFOFTJOUIFWFOUSJDMFTPGSBCCJUFTUBCMJTIFECZWPMVNFPWFSMPBEPQFSBUJPOGPMMPXFEXJUIQSFTTVSF-PWFSMPBE5IFSFWFSTJCMFFGGFDUPGUIFTFDIBOHFTXJUICJTPQSPMPMXBT BMTPFWBMVBUFE5IF)'HSPVQFYIJCJUFEMFGUWFOUSJDVMBSFOMBSHFNFOU TZTUPMJDEZTGVODUJPO QSPMPOHBUJPOPGDPSSFDUFE25JOUFSWBM 25D

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

*/530%6$5*0/ ƿ

5IJTXPSLXBTTVQQPSUFECZUIF4UBUF,FZ1SPHSBNPGUIF/BUJPOBM /BUVSBM4DJFODF'PVOEBUJPOPG$IJOB /P  $PSSFTQPOEJOHBVUIPS"JRVO.B .% %FQBSUNFOUPG$BSEJPWBTDVMBS.FEJDJOF UIF'JSTU"GGJMJBUFE)PTQJUBMPG.FEJDBM4DIPPM 9J’BO +JBPUPOH6OJWFSTJUZ :BOUB8FTU3PBE 9J’BO 4IBBOYJ  $IJOB C,FZ-BCPSBUPSZPG.PMFDVMBS$BSEJPMPHZPG4IBBOYJ1SPWJODF  :BOUB8FTU3PBE 9J’BO 4IBBOYJ $IJOB D,FZ-BCPSBUPSZPG&OWJSPONFOUBOE(FOFT3FMBUFEUP%JTFBTFT 9J’BO+JBPUPOH 6OJWFSTJUZ :BOUB8FTU3PBE 9J’BO 4IBBOYJ $IJOB5FM 'BY -- -- &-NBJMNBBJRVO!NFENBJM DPNDO 5IFTFBVUIPSTSFQPSUFEOPDPOGMJDUPGJOUFSFTUT

)FBSUGBJMVSFJTBDMJOJDBMTZOESPNFDBVTFECZWBSJPVT JNQBJSNFOUT JO DBSEJBD GVODUJPO4VEEFO EFBUI  BTTPDJBUFE XJUI BSSIZUINJB  JT SFTQPOTJCMF GPS BQQSPYJNBUFMZIBMGPGNPSUBMJUZSBUFBNPOHQBUJFOUTXJUI IFBSUGBJMVSF<>3FNPEFMJOHPGJPODIBOOFMTBOEJPOUSBOTQPSUGVODUJPOBSFBOJNQPSUBOUNFDIBOJTNPGBSSIZUINJBJOEVDFECZEJTFBTFEIFBSU5IFQSPMPOHFE BDUJPOQPUFOUJBMEVSBUJPO "1%

BTTPDJBUFEXJUIFBSMZ BGUFS-EFQPMBSJ[BUJPO &"%

JTBDPOTJTUFOUGJOEJOHJO UIFWFOUSJDVMBSNZPDZUFTPGQBUJFOUTXJUIIFBSUGBJMVSF

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Į-TVCVOJU ,W-25 BOE ȕ-TVCVOJU NJO, JOSBCCJU IFBSUGBJMVSFNPEFMJOEVDFECZWFOUSJDVMBSUBDIZDBSEJB<>5IFDIBOHFPG*,SVOJUT&3(IBTCFFODPOTJTUFOU 'FXTUVEJFTIBWFSFQPSUFESFEVDUJPOPG&3(<>4JNJMBS EJTDSFQBODJFTFYJTUJOUIFTUVEZPG*,VOJU,JS< > 'VSUIFSNPSF  BMUIPVHI UIF CFOFGJDJBM FGGFDUT PG ȕ- CMPDLFS UIFSBQZ IBWF CFFO LOPXO GPS RVJUF B XIJMF<-> UIFJSFYBDUNFDIBOJTNTPGBDUJPOTUJMMSFNBJO JODPNQMFUFMZ VOEFSTUPPE 4UVEJFT SFQPSU UIBU NPTUPGJPOJDDVSSFOUTBGGFDUFECZ ȕ-BESFOFSHJDTUJNVMBUJPOBSFBMTPBMUFSFECZȕ-CMPDLFST< >*OUIFQSFTFOU TUVEZ XFFYQMPSFEUIFQSPMPOHBUJPOPGUIF25JOUFSWBM BOEEPXO-SFHVMBUJPOPG, DIBOOFMFYQSFTTJPOJOSBCCJUIFBSUGBJMVSFNPEFMJOEVDFECZWPMVNF-PWFSMPBE DPNCJOFEXJUIQSFTTVSFPWFSMPBE5IFSFWFSTJCJMJUZPG UIFTFDIBOHFTXJUICJTPQSPMPMXBTBMTPEFNPOTUSBUFE

."5&3*"-4"/%.&5)0%4 "OJNBMHSPVQTBOENBUFSJBMT 5IJSUZ-POFNBMF/FX;FBMBOESBCCJUTXFJHIJOH LHBOELHXFSFPCUBJOFEGSPN9J’BO+JBPUPOH6OJWFSTJUZ-BCPSBUPSJBM"OJNBM$FOUFS 4IBBOYJ $IJOB  "MMBOJNBMTSFDFJWFEIVNBOFDBSFJODPNQMJBODFXJUI UIF(VJEFGPSUIF$BSFBOE6TFPG-BCPSBUPSZ"OJNBMT QVCMJTIFECZUIF64/BUJPOBM*OTUJUVUFPG)FBMUI /*) 1VCMJDBUJPO /P- SFWJTFEJO "EEJUJPOBMMZ  BMM FYQFSJNFOUBM QSPDFEVSFT XFSF BQQSPWFE CZ UIF $BSFPG&YQFSJNFOUBM"OJNBMT$PNNJUUFFPGUIF'JSTU "GGJMJBUFE )PTQJUBM PG .FEJDBM 4DIPPM  9J ’BO +JBPUPOH6OJWFSTJUZ 4IBBOYJ $IJOB"GUFSFWBMVBUJPOCZ FDIPDBSEJPHSBQIZ UIFSBCCJUTXFSFSBOEPNMZEJWJEFE JOUPUISFFHSPVQT OBNFMZ TIBN-PQFSBUJPOSBCCJUTBT UIF DPOUSPM HSPVQ $5-  O

 IFBSU GBJMVSF HSPVQ )' O BOEIFBSUGBJMVSFXJUICJTPQSPMPMUSFBUNFOU HSPVQ #JTP O  "MM TVQQMFNFOUT XFSF QVSDIBTFE BT GPMMPXT 5SJ[PMGSPN4JHNB 64"

4:#3嘐1SFNJY&Y5BR™** GSPN5BLBSB %BMJBO $IJOB

SBCCJU#/1&-*4"LJU GSPN 9JUBOH 4IBOHIBJ #JPMPHJDBM 5FDIOPMPHZ $P  -UE 4IBOHIBJ  $IJOB

 CJTPQSPMPM GVNBSBUF UBCMFUT GSPN.FSDL4FSPOP (FSNBOZ

BOE'DBUIFUFSGSPN

ǂ

$PSEJT 64"  &TUBCMJTINFOUPGIFBSUGBJMVSFNPEFM *OEVDUJPOPGIFBSUGBJMVSFNPEFMXBTQFSGPSNFEBDDPSEJOHUPUIFNFUIPEPG%FO<>XJUITPNFNPEJGJDBUJPOT*OCSJFG GPMMPXJOHJOEVDUJPOPGBOFTUIFTJB TPEJVNQFOUPCBSCJUBM NHLH JQ

B'DBUIFUFSXBT JOUSPEVDFEJOUPUIFSJHIUDBSPUJEBSUFSZUPJOEVDFBPSUJD JOTVGGJDJFODZ CZ SFQFBUFEMZ NPWJOH UIF DBUIFUFS UP BOEGSPBDSPTTUIFBPSUJDWBMWFVOUJMUIFQVMTFQSFTTVSF JODSFBTFECZ"GUFSX SBCCJUTXFSFBOFTUIFUJ[FEUPJOEVDFQSFTTVSFPWFSMPBEBTEFTDSJCFEBCPWF 5ISPVHIBNJE-BCEPNJOBMJODJTJPOUIFBPSUBXBTGSFFE GSPNUIFBEKBDFOUUJTTVFTBUBQPJOUKVTUBCPWFUIFSFOBMBSUFSJFT"TUBJOMFTTTUFFMSPE FYUFSOBMEJBNFUFSPG NN XBTQMBDFEOFYUUPUIFBPSUB"MJHBUVSFXBT UJFEBSPVOEUIFBPSUBBOESPEBGUFSXIJDIUIFSPEXBT SFNPWFE5IJTSFTVMUFEJOBSFEVDUJPOPGUIFBPSUJDEJBNFUFSPGBQQSPYJNBUFMZ*OTIBNPQFSBUFESBCCJUT UIFSJHIUDBSPUJEBSUFSZBOEBCEPNJOBMBPSUBXBT POMZGSFFEGSPNUIFBEKBDFOUUJTTVFT"GUFSJOEVDUJPO  UIF #JTP HSPVQ SBCCJUT CFHBO UP SFDFJWF CJTPQSPMPM USFBUNFOU NHLHE CZHBTUSJDMBWBHFGPSBCPVUX

&WBMVBUJPOPGIFBSUGVODUJPO "GUFSXPGJOEVDUJPOPGQSFTTVSFPWFSMPBE SBCCJU IFBSUGVODUJPOPGUIFUISFFHSPVQTXBTNPOJUPSFECZ FDIPDBSEJPHSBQIJDNFBTVSFNFOUT-FGUBSUFSJBMEJBNFUFS -"%

BPSUJDEJBNFUFS "0%

MFGUWFOUSJDVMBS FOE-EJBTUPMJDEJNFOTJPO -7%%

MFGUWFOUSJDVMBSFOETZTUPMJDEJNFOTJPO -7%4

MFGUWFOUSJDVMBSQPTUFSJPS XBMM -718

JOUFSWFOUSJDVMBSTFQUBMUIJDLOFTT *745

 FKFDUJPOGSBDUJPO &'

GSBDUJPOBMTIPSUFOJOH '4

BOE FBSMZEJBTUPMJDGJMMJOHUPBUSJBMGJMMJOHWFMPDJUZSBUJPPG NJUSBM GMPX &"  XFSF NFBTVSFE 25 JOUFSWBM XBT NFBTVSFEVTJOHBTUBOEBSEMFBE**FMFDUSPDBSEJPHSBN &$( 5IF25JOUFSWBMXBTDPSSFDUFE 25D BDDPSEJOHUP$BSMTTPO’TGPSNVMB<>GPSSBCCJUTXJUI25D 25- 33-

BOE CSBJO OBUSJVSFUJD QFQUJEF #/1 JOCMPPEXBTNFBTVSFEVTJOHFO[ZNF-MJOLFE JNNVOPTPSCFOUBTTBZ &-*4" LJU D%/" TZOUIFTJT BOE RVBOUJUBUJWF SFBM-UJNF 1$3BOBMZTJT 7FOUSJDVMBSUJTTVF3/"JTPMBUJPOBOESFWFSTFUSBOTDSJQUJPOXFSFDBSSJFEPVUVTJOHUIF4VQFSTDSJQUGJSTUTUSBOETZOUIFTJTTZTUFN 5BLBSB %BMJBO $IJOB BDDPSEJOHUPUIFNBOVGBDUVSFS’TJOTUSVDUJPOT4QFDJGJD QSJNFST GPS SBCCJU ,JS  ,W  ,W  ,W-25  NJO, &3(BOE("1%)BSFTIPXOJO 5BCMF3FBMUJNF1$3XBTQFSGPSNFEPOBOJ23FBM-5JNF1$3 %FUFDUJPO4ZTUFN #*0-3"% 64" VTJOHUIF4:#3嘐 1SFNJY&Y5BR™** 5BLBSB %BMJBO $IJOB XJUIBO JOJUJBMDZDMFPG°$GPSTGPMMPXFECZDZDMFTPG

ǂ

9J-FUBM+PVSOBMPG#JPNFEJDBM3FTFBSDI     5BCMF4QFDJGJDQSJNFSTGPSSBCCJUUBSHFUHFOFT

(FOF

(FOF*%

1SJNFS -

,JS

/.

,W

/$

,W

/$

,W-25

/8

NJO,

/8

&3(

/8

("1%)

/$

'"$5$$$$5(5(5"(5($$"(" 3($$5((55(5(""((5$""5( '($$($"(5""(""("$$"$"$ 355((5$5$"(5$$(5$(5$5( '$"($"($""$"(($$"5(5$ 3$5$$($("""5"$"$"($$5 '($$($"($"(5"5(5$( 3$$55$5$"($"((5"$"$(" '("("$(($$$"$$5"$(( 3$(""(""($$("($"$$"5 '5$($"$$"55"($""("55$ 3(("5("($$"(5$$$"$"

4J[F CQ

5. °$





























'$5$5(((($5(5(($(5 3($5$(((("5("$$55($

°$GPSTBOE°$GPST3FMBUJWFRVBOUJUBUJPO PGUBSHFUHFOFFYQSFTTJPOOPSNBMJ[FEUP("1%)XBT -ǻǻ $ DBMDVMBUFEBDDPSEJOHUPUIF NFUIPE

5BCMF  $IBSBDUFSJTUJDT PG IFBSU GVODUJPO NFBTVSFNFOUJOUIFUISFFHSPVQT

5

4UBUJTUJDBMBOBMZTJT %BUB XFSF FYQSFTTFE BT NFBOf4&. 4UBUJTUJDBM DPNQBSJTPOT CFUXFFO UXP HSPVQT XFSF QFSGPSNFE XJUIPOF-XBZ"/07"UFTU%JGGFSFODFTXFSFDPOTJEFSFETJHOJGJDBOUBU1

$5-

)'

#JTP

-"% NN

f

f

f 

"0% NN

f

f

f 

-7%% NN

f

f

f 

f



f 



f 



-7%4 NN

-718 NN

3&46-54

f

f

*745 NN

f

f

f 

&' 

f

f

f 

f



f 



f 



f 

'4 NN

$IBSBDUFSJTUJDTPGIFBSUGVODUJPOPGUIFUISFF HSPVQT )FBSU GBJMVSF XBT DPOGJSNFE CZ CPUI FDIPDBSEJPHSBQIJDFYBNJOBUJPOBOE QMBTNB#/1MFWFMUFTUBU XFFLTBGUFSUIFQSFTTVSFPWFSMPBEJOEVDUJPO"TTIPXO JO 5BCMF   DPNQBSFE XJUI UIPTF PG DPOUSPM SBCCJUT  -"%  "0%  -7%%  -7%4  -718  *745  BOE '4 JODSFBTFE BOE &' EFDSFBTFE TJHOJGJDBOUMZ JO IFBSU GBJMVSF SBCCJUT 'VSUIFSNPSF  QMBTNB #/1 MFWFM  B WBMVBCMF NBSLFS PG IFBSU GBJMVSF <>  BMTP JODSFBTFE TJHOJGJDBOUMZJOIFBSUGBJMVSFSBCCJUT"GUFSCJTPQSPMPM USFBUNFOU &' '4BOE&"PGIFBSUGBJMVSFSBCCJUTXFSF JODSFBTFETJHOJGJDBOUMZ DPNQBSFEXJUIIFBSUGBJMVSF SBCCJUT*OBEEJUJPO #/1MFWFMEFDSFBTFE

f

&"

f

f

#/1 ONPM-

f

f

f



1WTDPOUSPMHSPVQ $5- 1WTIFBSUGBJMVSFHSPVQ )'  "0%BPSUJDEJBNFUFS#/1CSBJOOBUSJVSFUJDQFQUJEF&"FBSMZEJBTUPMJDGJMMJOHUPBUSJBMGJMMJOHWFMPDJUZSBUJPPGNJUSBMGMPX&'FKFDUJPO GSBDUJPO'4GSBDUJPOBMTIPSUFOJOH*745JOUFSWFOUSJDVMBSTFQUBMUIJDLOFTT-"%MFGUBSUFSJBMEJBNFUFS-7%%MFGUWFOUSJDVMBSFOE-EJBTUPMJD EJNFOTJPO-7%4MFGUWFOUSJDVMBSFOE-TZTUPMJDEJNFOTJPO-718MFGU WFOUSJDVMBSQPTUFSJPSXBMM

5BCMF*OWJWPNFBTVSFNFOUT $5)'

#PEZXFJHIU LH

)FBSUSBUF

25JOUFSWBM NT

f

f

f

f

f

f

f



f

25D NT



#JTP f f f f   1WTDPOUSPM $5-

 1WTIFBSUGBJMVSF )' 25DDPSSFDUFE25JOUFSWBM



&$(DIBOHFT 5BCMF  TIPXT 25 BOE 25D JO FMFDUSPDBSEJPHSBIJD SFTVMUT GSPN UIF UISFF HSPVQT *O UIF )' HSPVQ  25BOE25DJODSFBTFEUP f NTBOE f  NT SFTQFDUJWFMZ)PXFWFS 25BOE25DJODSFBTFEUP f NTBOE f NT SFTQFDUJWFMZ JO#JTP HSPVQ &YQSFTTJPOPG*UPTVCVOJUN3/" 5IF FYQSFTTJPO PG *UP TVCVOJU N3/" XBT FWBMV-

BUFE"TTIPXOJO 'JH UIFFYQSFTTJPOPG,WXBT TJHOJGJDBOUMZEPXO-SFHVMBUFECZJOUIF)'HSPVQ 1    *O UIF #JTP HSPVQ  FYQSFTTJPO PG ,W XBTSFEVDFECZ 1 4JNJMBSSFTVMUTXFSF PCUBJOFEGPS,WN3/"FYQSFTTJPO SFEVDUJPOXBT JOUIF)'HSPVQ 1

CVUJOUIF#JTP HSPVQ 1 

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













,W

,W $5-)'#JTP

'JH)JTUPHSBNDPNQBSJOHSFMBUJWFBNPVOUTPGUIF QPUBTTJVNDIBOOFMJTPGPSN,WBOE,WN3/"JO UIFWFOUSJDVMBSNZPDBSEJVNPGSBCCJUTGSPNUIFUISFF HSPVQT 1$5-UIFDPOUSPMHSPVQ)'UIFIFBSUGBJMVSFHSPVQ#JTPUIFCJTPQSPMPMHSPVQ











&3(

NJO,

,W-25

$5-)'#JTP

'JH  3FBM-UJNF 1$3 SFTVMUT PG ,W-25  NJO, BOE &3(&YQSFTTJPOPG,W-25XBTfJOUIF)'SBCCJUT  f JO UIF #JTP HSPVQ &YQSFTTJPO PG NJO, XBT fJOUIF)'SBCCJUT fJOUIF#JTPHSPVQ 1   1$5-UIFDPOUSPMHSPVQ)'UIFIFBSUGBJMVSF HSPVQ#JTPUIFCJTPQSPMPMHSPVQ





ǂ







 $5-)'#JTP

'JH3FBM-UJNF1$3SFTVMUTPG,JS3FMBUJWFGPMEPG FYQSFTTJPO PO ,JS XBT f BOE f JO UIF )'HSPVQBOE#JTPHSPVQ SFTQFDUJWFMZ 1$5-UIF DPOUSPMHSPVQ)'UIFIFBSUGBJMVSFHSPVQ#JTPUIFCJTPQSPMPM HSPVQ

%*4$644*0/ *OUIJTTUVEZ XFGPVOEUIBUUIFFYQSFTTJPOPGTFWFSBMHFOFTFODPEJOHQPUBTTJVNDIBOOFMJTPGPSNT *UP  *,TBOE*,TVCVOJUT XBTEPXO-SFHVMBUFEJOUIFIFBSU PGSBCCJUTXJUIWPMVNFDPNCJOFEXJUIQSFTTVSFPWFSMPBEIFBSUGBJMVSF5IJTNBZBDDPVOUGPSUIFQSPMPOHBUJPOPG"1%PGWFOUSJDVMBSNZPDZUFT5SFBUNFOUXJUI CJTPQSPMPM B ȕ-CMPDLFST DPVMEQBSUJBMMZSFWFSTFUIFTF EPXO-SFHVMBUJPOTBOEJNQSPWFIFBSUGVODUJPO 3BCCJUTIBWFBEJTUJODUQMBUFBVTUBHFJOBDUJPOQPUFOUJBM BOE B TJNJMBS FYQSFTTJPO PG ,  DIBOOFMT UP IVNBO’T *O PVS TUVEZ  UIF IFBSU GBJMVSF NPEFM XBT JOEVDFE JO SBCCJUT CZ WPMVNF-PWFSMPBE DPNCJOFE XJUIQSFTTVSF-PWFSMPBEQSPDFEVSFBOEDPOGJSNFECZ FDIPDBSEJPHSBQIJDFYBNJOBUJPOBOEQMBTNB#/1MFWFM UFTU5IFNPEFMXJUICPUITZTUPMJDBOEEJBTUPMJDEZTGVODUJPOTIBTBTJNJMBSQBUIPQIZTJPMPHZUPBIVNBO POF JODMVEJOHWFOUSJDVMBSIZQFSUSPQIZBOEEJMBUBUJPO  DPNCJOFE XJUI EFDSFBTFE &' BOE '4  XFFLT BGUFS TVSHFSZ CZ FDIPDBSEJPHSBQIZ 1MBTNB #/1 XBT JODSFBTFETJHOJGJDBOUMZBOE25DXBTQSPMPOHFEJO&$( PGGBJMJOHIFBSU 1PUBTTJVNDVSSFOUTQMBZBLFZSPMFJOUIFGPSNBUJPO PG"1%<>5SBOTJFOUPVUXBSEDVSSFOU *UP FODPEFECZ ,WBOE,W JTUIFNBJODVSSFOUJOQIBTFFBSMZ SBQJESFQPMBSJ[BUJPO1IBTFJTBMBUFSFQPMBSJ[BUJPO QIBTFPG"1%EPNJOBUFECZ*,S FODPEFECZ&3(BOE NJO, BOE*LT FODPEFECZ,W-25BOENJO, *, FODPEFECZ,JS JTBEFUFSNJOBOUGBDUPSGPSNBJOUFOBODFPGSFTUJOHQPUFOUJBMJOQIBTF"1%JTTIPXO BT25JO&$(DMJOJDBMMZ1SPMPOHFE25DJTDPOTJTUFOU XJUIGJOEJOHTJOTUVEJFTPGIVNBOBOEBOJNBMIFBSU GBJMVSFNPEFMT< > 4UVEJFTIBWFTIPXOUIBUSFQPMBSJ[BUJPOBCOPSNBMJUJFTBOE25"1%QSPMPOHBUJPONBZCFEVFUPDIBOHFT PG ,  DVSSFOUT JOEVDFE CZ IFBSU GBJMVSF< > *O PVS

ǂ

9J-FUBM+PVSOBMPG#JPNFEJDBM3FTFBSDI    

TUVEZ UIFSFXBTBSFEVDUJPOJON3/"MFWFMPG,W CZ ,WCZ ,W-25CZ NJO,CZ  BOE ,JS CZ  JO UIF MFGU WFOUSJDMFT GSPN UIFIFBSUGBJMVSFSBCCJU)PXFWFS &3(N3/"XBT OPUPCTFSWFEXJUIHSFBUDIBOHFT4VDISFNPEFMJOHPG ,  DIBOOFM FYQSFTTJPO XBT BDDPNQBOJFE XJUI 25D QSPMPOHBUJPO0VSEBUBBSFJOBHSFFNFOUXJUIUIPTFPG QSFWJPVTTUVEJFTJOUIFGBJMJOHWFOUSJDMFTGSPNIVNBO BOEBOJNBMNPEFMT*OSBCCJUGBJMJOHIFBSUJOEVDFECZ UBDIZQBDJOH TUVEJFTTIPXFEUIBU ,W ,W ,W-25 BOE NJO, N3/" XFSF SFEVDFE<> *O DBOJOF IFBSUGBJMVSFNPEFMJOEVDFECZUBDIZQBDJOH BTJHOJGJDBOUEFDSFBTFJO,WN3/"<>IBTCFFOGPVOE*O UIFIVNBOGBJMJOHIFBSU ,JSBOE,WN3/"XBT NFBTVSFEXJUIBTUSJLJOHEFDSFBTFCZHFOFNJDSPBSSBZ BOBMZTJT XIJMF,W-25 NJO,BOE&3(N3/"XFSF GPVOE<> 1SPMPOHBUJPO PG 25 PS "1%  SFGMFDUJOH JNQBJSFE SFQPMBSJ[BUJPO  JT B DPOTJTUFOU GJOEJOH JO QSFWJPVT TUVEJFT< >&BSMZBGUFS-EFQPMBSJ[BUJPOT &"%T BOE EFMBZFE BGUFS-EFQPMBSJ[BUJPOT %"%  BSF UIF IFBSU GBJMJOH-JOEVDFEBSSIZUINJBTXIJDIBSFBTTPDJBUFEXJUI SFNPEFMJOH PG ,  DVSSFOUT &"% DPNNPOMZ PDDVST JOQIBTFBOEQIBTFPG"1%&"%JTUIFSFTVMUPG SFEVDUJPOPG*,T *,S *UPBOE*,< >%"%TBSFGBWPSFE CZJODSFBTFE/B -$B FYDIBOHFBOESFEVDFE*,3FNPEFMJOHPG, DVSSFOUTQMBZTBLFZSPMFJODBSEJBDBSSIZUINJBTBTTPDJBUFEXJUIIFBSUGBJMJOH5IFEFDSFBTF PGN3/"FYQSFTTJPOPG, DIBOOFMTTVCVOJUTVOEFSMJFTUIFNPMFDVMBSEPXO-SFHVMBUJPOPG, DVSSFOUT<> #JTPQSPMPMIBTCFFODPOGJSNFEUPCFCFOFGJDJBMGPS TIPSUFOJOHQSPMPOHFE25JOEVDFECZIFBSUGBJMVSFJO DMJOJDBMUSJBMTBOEBOJNBMFYQFSJNFOUT< >0VSQSFTFOU TUVEZJTJOBHSFFNFOUXJUIQSFWJPVTSFQPSUT0VSQSFWJPVTTUVEZPOIFBSUGBJMVSFSBUTTIPXFEBTJHOJGJDBOU SFEVDUJPOPG*UPBOE*,BOEFYQSFTTJPOPG*UPBOE*,BU UIFQSPUFJOMFWFM8FBMTPGPVOEUIBUCJTPQSPMPMDPVME SFWFSTFUIFEPXO-SFHVMBUJPOPG*,S *UPBOE*,5IFJOUFSFTUJOHGJOEJOHTTIPXFEJOPVSTUVEZBSFUIBUCJTPQSPMPM DPVME SFWFSTF EPXO-SFHVMBUJPO PG ,  DVSSFOU FYQSFTTJPO5IFTFGJOEJOHTNBZVOEFSMJFUIFNPMFDVMBS NFDIBOJTNGPSBOUJBSSIZUINJBPGCJTPQSPMPM *PO-DIBOOFMGVODUJPOJTSFHVMBUFECZDIBOOFMQIPTQIPSZMBUJPOTUBUF OFVSPUSBOTNJUUFST BOEJOUFSBDUJPOT XJUI PUIFS DIBOOFMT BOE USBOTQPSUFST *O DMBTTJD ȕBESFOPDFQUPS-NFEJBUFE TJHOBMJOH JO DBSEJPNZPDZUF  QSPUFJO LJOBTF " 1,"  QBTTXBZ BDUJWBUFE WJB TFDPOEBSZ NFTTFOHFS D".1 DBO QIPTQIPSZMBUF NBOZ QSPUFJOTJOWPMWFEJOJPODIBOOFMTSFTVMUJOHJODIBOHFT PGUIFJSLJOFUJDQSPQFSUJFTȕ-"ESFOFSHJDTUJNVMBUJPO WJBD".1-EFQFOEFOU1,"NFDIBOJTNFOIBODFT*, BOE*,TDVSSFOU<>XIJMFEFDSFBTFT)&3( Į-TVCVOJUPG *,S DVSSFOUCZ-<>)PXFWFS FYBDUNFDIB-

OJTNPG ȕ-CMPDLFSTNPEVMBUJOHUIFSFNPEFMJOHPGQPUBTTJVNDIBOOFMTJODBSEJPNZPDZUFXFSFTUJMMVODMFBS &YQFSJNFOUTXJUIJTPQSPUFSFOPMBOE ȕ-CMPDLFSTEFNPOTUSBUFE UIBU *, JT BGGFDUFE CZ 1," QIPTQIPSZMBUJPO<>5IFSFTVMUTBMTPTVHHFTUFE ȕ-CMPDLFSTTVQQSFTT BESFOFSHJDTUJNVMBUJPOBOEBMUFS1,"UPSFHVMBUFQPUBTTJVNDIBOOFMT *O TVNNBSZ  PVS EBUB EFNPOTUSBUFE UIBU EPXOSFHVMBUFEFYQSFTTJPOPGQPUBTTJVNDIBOOFMJTPGPSNT ,WBOE,W FODPEJOH*UPTVCVOJU

,W-25BOE NJO, GPS*, BOE,JS GPS*, NBZDPOUSJCVUFUP UIFQSPMPOHBUJPOPG"1%JOUIFIFBSUPGSBCCJUTXJUI WPMVNFDPNCJOFEXJUIQSFTTVSFPWFSMPBEIFBSUGBJMVSF "EEJUJPOBMMZ USFBUNFOUXJUICJTPQSPMPM B ȕ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

#JTPQSPMPMSFWFSTFTEPXO-SFHVMBUFEQPUBTTJVNDIBOOFMJO)' QJUBMJ[FEXJUIIFBSUGBJMVSF+"N$PMM$BSEJPM - <> "OPZNPVT5IFDBSEJBDJOTVGGJDJFODZCJTPQSPMPMTUVEZ** $*#*4-** BSBOEPNJ[FEUSJBM-BODFU- <>%F1FVUFS03 4PVWFSFJO1$ ,MVOHFM0) #ü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

ǂ

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

* UP T

 * , TMPX

* , TMPX

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’"SNJFOUP + .BSLT"3 FUBM3FRVJSFNFOUPGBNBDSPNPMFDVMBS TJHOBMJOHDPNQMFYGPSCFUBBESFOFSHJDSFDFQUPSNPEVMBUJPOPGUIF,$/2–,$/&QPUBTTJVNDIBOOFM4DJFODF - <>-J(3 'FOH+ 8BOH; 'FSNJOJ# /BUUFM4"ESFOFSHJD NPEVMBUJPOPGVMUSBSBQJEEFMBZFESFDUJGJFS, DVSSFOUJO IVNBOBUSJBMNZPDZUFT$JS3FT-