• No results found

Studies on leptospirosis : clinical aspects and pathophysiology - Chapter 9: Innate immune response to pathogenic leptospira is dependent of both TLR2 and TLR4 signaling in human whole blood.

N/A
N/A
Protected

Academic year: 2021

Share "Studies on leptospirosis : clinical aspects and pathophysiology - Chapter 9: Innate immune response to pathogenic leptospira is dependent of both TLR2 and TLR4 signaling in human whole blood."

Copied!
27
0
0

Bezig met laden.... (Bekijk nu de volledige tekst)

Hele tekst

(1)

UvA-DARE is a service provided by the library of the University of Amsterdam (https://dare.uva.nl)

UvA-DARE (Digital Academic Repository)

Studies on leptospirosis : clinical aspects and pathophysiology

Wagenaar, J.F.P.

Publication date

2010

Link to publication

Citation for published version (APA):

Wagenaar, J. F. P. (2010). Studies on leptospirosis : clinical aspects and pathophysiology.

General rights

It is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), other than for strictly personal, individual use, unless the work is under an open content license (like Creative Commons).

Disclaimer/Complaints regulations

If you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Ask the Library: https://uba.uva.nl/en/contact, or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You will be contacted as soon as possible.

(2)

,QQDWHLPPXQHUHVSRQVHWRSDWKRJHQLF

/HSWRVSLUDLVGHSHQGHQWRIERWK7/5DQG7/5

VLJQDOLQJLQKXPDQZKROHEORRG

-)3:DJHQDDU 0*$*RULV 5$+DUWVNHHUO(&0YDQ*RUS-(1DOO\

$00RQDKDQ7YDQGHU3ROODQG&YDQ·W9HHU 'HSDUWPHQWRI,QWHUQDOPHGLFLQH6ORWHUYDDUW+RVSLWDO$PVWHUGDPWKH1HWKHUODQGV 5R\DO7URSLFDO,QVWLWXWH .,7 .,7ELRPHGLFDO5HVHDUFK$PVWHUGDPWKH1HWKHUODQGV 9HWHULQDU\6FLHQFHV&HQWUH6FKRRORI$JULFXOWXUH)RRG6FLHQFH 9HWHULQDU\0HGLFLQH &ROOHJHRI/LIH6FLHQFHV8QLYHUVLW\&ROOHJH'XEOLQ%HOÀHOG'XEOLQ,UHODQG &HQWHUIRU([SHULPHQWDODQG0ROHFXODU0HGLFLQH$PVWHUGDPWKH1HWKHUODQGV &HQWHUIRU,QIHFWLRQDQG,PPXQLW\$PVWHUGDP &,1,0$ 8QLYHUVLW\RI$PVWHUGDP $PVWHUGDPWKH1HWKHUODQGV %RWKDXWKRUVHTXDOO\FRQWULEXWHG 6XEPLWWHG



&+$37(5

(3)

&KDSWHU



/HSWRVSLURVLV LV FDXVHG E\ SDWKRJHQLF VSLURFKHWHV RI WKH JHQXV /HSWRVSLUD %HLQJ VSUHDG E\ WKH XULQH RI LQIHFWHG DQLPDOV WKH EDFWHULD HQWHU WKH KXPDQ ERG\ YLD DEUDGHGVNLQRUPXFRXVPHPEUDQHVDQGUDSLGO\GLVVHPLQDWHWKURXJKRXWWKHERG\ 0RVWO\ WKH LOOQHVV LV PLOG EXW VRPH SDWLHQWV GHYHORS UDSLGO\ SURJUHVVLYH VHYHUH GLVHDVHZLWKDKLJKFDVHIDWDOLW\UDWH1RWPXFKLVNQRZQDERXWWKHLQQDWHLPPXQH UHVSRQVHWR/HSWRVSLUD3UHYLRXVZRUNVKRZHGWKDWDKXPDQPRQRF\WLFFHOOOLQH 7+3   UHFRJQL]HG KHDWNLOOHG /HSWRVSLUD DQG OHSWRVSLUDO /36 WKURXJK 7/5 LQVWHDG RI 7/5DVIRUW\SLFDOJUDPQHJDWLYH/36:HLQYHVWLJDWHGLPPXQHUHVSRQVHVWRGLYHUVH OLYHOHSWRVSLUDOVHURYDUV.LOOLQJDQGVWLPXODWLRQH[SHULPHQWVZHUHGRQHXVLQJ7+3 KXPDQ3%0&DQGZKROHEORRG:HH[DPLQHGWKHLQYROYHPHQWRI7/5DQG7/5 VLJQDOLQJ6DSURSK\WLFDQGSDWKRJHQLFUHIHUHQFHVWUDLQVEXWQRWIUHVKKRVWDGDSWHG /HSWRVSLUDZHUHNLOOHGE\ZKROHEORRGDQGVHUXP/LYH/HSWRVSLUDLQGXFHGDYLJRURXV VHURYDUGHSHQGHQWF\WRNLQHUHVSRQVH3%0&ZDVPRUHVHQVLWLYHWR/HSWRVSLUDWKDQ 7+3DQGZKROHEORRGZDVPRUHVHQVLWLYHWKDQ3%0&,QKLELWLRQH[SHULPHQWVZLWK DQWL7/5DQGDQWL7/5DQWLERGLHVLQZKROHEORRGVKRZHGLQYROYHPHQWRIERWK7/5 DQG7/57KHLU VLJQDOLQJ ZDV DGGLWLYH LQ FDVH RI UHIHUHQFH VHURYDU %DWDYLDH DQG V\QHUJLVWLFLQFDVHRILWVKRVWDGDSWHGFRXQWHUSDUW7KLVVWXG\UHYHDOVWKUHHÀQGLQJV ZLWKDPDMRULPSDFWRQWKHLQYHVWLJDWLRQRILPPXQHUHVSRQVHVDJDLQVWOHSWRVSLUHV LQIHFWLRQ L ERWK7/5DQG7/5DUHLQYROYHGLQWKHLQQDWHLPPXQHUHVSRQVH LL  LPPXQHUHVSRQVHVDUH IRUSDUW VHURYDUGHSHQGHQW LLL IUHVKLVRODWHVDUHQHHGHGWR EHWWHUPLPLFQDWXUDOLQIHFWLRQ



$%675$&7

(4)

,QQDWHLPPXQHUHVSRQVHWRSDWKRJHQLF

/HSWRVSLUD

 /HSWRVSLURVLVWUDQVPLVVLRQRFFXUVZRUOGZLGHDQGFRPSULVHVDOOLQIHFWLRQVFDXVHGE\

SDWKRJHQLF VSLURFKHWHV RI WKH JHQXV /HSWRVSLUD &XUUHQWO\ RYHU  VHURYDUV DUH NQRZQWUDGLWLRQDOO\JURXSHGLQWRVHYHUDOVHURJURXSV%HLQJVSUHDGE\WKHXULQHRI LQIHFWHGDQLPDOVWKHEDFWHULDHQWHUWKHKXPDQERG\YLDDEUDGHGVNLQFRQMXQFWLYDH RUPXFRXVPHPEUDQHVDIWHUZKLFKWKH\UDSLGO\GLVVHPLQDWHWKURXJKRXWWKHERG\ 7KHPDMRULW\RILQIHFWLRQVDUHWKRXJKWWRUHVXOWLQDPLOGLOOQHVVZLWKUDWKHUQRQ VSHFLÀFV\PSWRPVOLNHIHYHUP\DOJLDDQGKHDGDFKH6RPHSDWLHQWVGHYHORSVHYHUH GLVHDVHZKLFKLVRIWHQUDSLGO\SURJUHVVLYHDQGFDQEHIDWDOLQXSWRRIFDVHV   7KH FOLQLFDO SLFWXUH LV GRPLQDWHG E\ KHSDWRUHQDO LPSDLUPHQW DQG KHPRUUKDJHV 3DWLHQWV XVXDOO\ GLH IURP VHSWLF VKRFN ZLWK PXOWLRUJDQ IDLOXUH DQGRU RYHUW SXOPRQDU\ KHPRUUKDJHV3DWKRORJLFDOÀQGLQJVUHYHDOZLGHVSUHDGKDHPRUUKDJLQJLQ YLUWXDOO\DOORUJDQVDQGWLVVXHVZLWKGLIIXVHLQÁDPPDWRU\LQÀOWUDWHV  /HSWRVSLUD DQWLJHQKDVEHHQLGHQWLÀHGLQPDQ\RUJDQVLQFOXGLQJOXQJVOLYHUDQGNLGQH\V   ,W LV EHOLHYHG WKDW /HSWRVSLUD PLJUDWH WKURXJK LQWHUFHOOXODU MXQFWLRQV KRZHYHU HOHFWURQPLFURVFRS\GHPRQVWUDWHGEDFWHULDZLWKLQWKHF\WRSODVPQRWFRQWDLQHGLQD PHPEUDQHFRPSDUWPHQWRULQWHUFHOOXODUMXQFWLRQ  

,PPXQLW\ DJDLQVW /HSWRVSLUD GHSHQGV RQ WKH SURGXFWLRQ RI FLUFXODWLQJ DQWLERGLHV GLUHFWHGDJDLQVWVHURYDUVSHFLÀFOLSRSRO\VDFFKDULGHV /36 ,QWHUHVWLQJO\OHSWRVSLUDO /36GLIIHUVIURPJUDPQHJDWLYH/36LQVHYHUDOELRFKHPLFDOSK\VLFDODQGELRORJLFDO SURSHUWLHV  $OWKRXJKFUXFLDOLQHDUO\VWDJHLQIHFWLRQQRWPXFKLVNQRZQDERXWWKH LQQDWHLPPXQHUHVSRQVHWR/HSWRVSLUD6HYHUDOF\WRNLQHVVXFKDVLQWHUIHURQ ,)1 γ LQWHUOHXNLQ ,/ S DQG 71)α DUH UHOHDVHG GXULQJ LQIHFWLRQ   $ KXPDQ PRQRF\WLF FHOO OLQH 7+3  WUDQVIHFWHG ZLWK KXPDQ &' ZDV DEOH WR UHFRJQL]H KHDWNLOOHG/HSWRVSLUDDQGOHSWRVSLUDO/36WKURXJKWROOOLNHUHFHSWRU 7/5 EXWQRW 7/5  7KLVÀQGLQJZDVXQLTXHVLQFH7/5LVFRQVLGHUHGWREHWKHSUHGRPLQDQW UHFHSWRU PHGLDWLQJ D /36 LQGXFHG F\WRNLQH UHVSRQVH 6XEVHTXHQW PXULQH PRGHOV XVLQJHLWKHUKHDWNLOOHGEDFWHULDRU/36VKRZHGHYLGHQFHWKDWERWK7/5DQG7/5 SOD\ D UROH   +RZHYHU WKHVH SUHYLRXV VWXGLHV PLJKW QRW EH UHSUHVHQWDWLYH RI WKH LPPXQH UHVSRQVH WR GLIIHUHQW VHURYDUV DQG YLDEOH /HSWRVSLUD +HQFH LQ WKH SUHVHQW VWXG\ ZH LQYHVWLJDWHG WKH LQQDWH LPPXQH UHVSRQVH WR VHYHUDO YLDEOH

(5)

&KDSWHU



OHSWRVSLUDO VHURYDUV .LOOLQJ DVVD\V DQG VWLPXODWLRQ H[SHULPHQWV ZHUH SHUIRUPHG XVLQJ D KXPDQ PRQRF\WLF FHOO OLQH 7+3  KXPDQ SHULSKHUDO EORRG PRQRQXFOHDU FHOOV 3%0&  DQG KXPDQ ZKROH EORRG 0RUHRYHU ZH H[DPLQHG WKH LQYROYHPHQW RI 7/5DQG7/5LQWKHFHOOXODUUHVSRQVLYHQHVVWROHSWRVSLUDOVHURYDUV

%DFWHULDDQGUHDJHQWV

/HSWRVSLUD VWUDLQV IURP WKH :+2)$22,( DQG 1DWLRQDO FROODERUDWLQJ FHQWUH IRU

UHIHUHQFHDQGUHVHDUFKRQ/HSWRVSLURVLV$PVWHUGDP7KH1HWKHUODQGVZHUHXVHG 6DSURSK\WLF QRQSDWKRJHQLF  UHIHUHQFH VWUDLQ /HSWRVSLUD ELÁH[D VHURYDU 3DWRF VWUDLQ3DWRF,3DWKRJHQLFUHIHUHQFHVWUDLQV/HSWRVSLUDLQWHUURJDQVVHURYDU%DWDYLDH VWUDLQ6ZDUWDQG/LQWHUURJDQVVHURYDU/DLVWUDLQ/DL7ZRIUHVKLVRODWHVIURPKXPDQ SDWLHQWV/LQWHUURJDQVVHURYDU%DWDYLDHVWUDLQ.DULDGL6DWXLVRODWHGLQIURP DQDGXOWPDOHDGPLWWHGDWWKH'U.DULDGL+RVSLWDOLQ6HPDUDQJ,QGRQHVLDLGHQWLÀHG E\FURVVDJJOXWLQLQDEVRUSWLRQWHVW &$$7   DQGVHTXHQFLQJ  IRUVHURYDUDQG VSHFLHVGHWHUPLQDWLRQDQG/LQWHUURJDQVVHURYDU/DLW\SH/DQJNDZLVWUDLQ/DQJNDZL UHVSHFWLYHO\  6WUDLQ.DULDGL6DWXZDVDOLTXRWHGDQGVWRUHGDW²ž&VKRUWO\DIWHU LVRODWLRQLHDWDPLQLPXPRILQYLWURSDVVDJHVWRPDLQWDLQWKHLQWHJULW\DVKXPDQ KRVWDGDSWHG YDULDQW RI WKH UHIHUHQFH VWUDLQ 6WUDLQ /DQJNDZL ZDV DOLTXRWHG DQG VWRUHGDW ƒ& RQH \HDUDIWHULVRODWLRQ DSSUR[LPDWHO\ SDVVDJHV /HSWRVSLUHV ZHUHJURZQLQOLTXLG(OOLQJKDXVHQ0F&XOORXJK-RKQVRQDQG+DUULVPHGLXP (0-+LQ KRXVHSUHSDUHG  )LIW\PORIDIXOOJURZQFXOWXUHZDVLQRFXODWHGLQWRPORI (0-+DWƒ&LQDVKDNLQJLQFXEDWRUIRUGD\V

)RUWKHH[SHULPHQWVOHSWRVSLUHVZHUHZDVKHGWLPHVZLWK530, ,QYLWURJHQ 3DLVOH\ 6FRWODQG 8.  WR UHPRYH SRVVLEOH /36 FRQWDPLQDWLRQ IURP WKH JURZWK PHGLXPFRXQWHGXVLQJD+HOEHU&RXQWLQJ&KDPEHU +DZNVOH\/DQFLQJ6XVVH[8.  XQGHUGDUNÀHOGPLFURVFRS\DQGUHVXVSHQGHGDWDFRQFHQWUDWLRQRI;EDFWHULD SHUPOIURPZKLFKIXUWKHUIROGGLOXWLRQVZHUHPDGHLQ530,7RKHDWNLOO ZDVKHG/HSWRVSLUDZHUHVXEMHFWHGWRDPLQXWHVWUHDWPHQWDWƒ&EHIRUHGLOXWLRQ LQDSSURSULDWHFRQFHQWUDWLRQV

0$7(5,$/6$1'0(7+2'6

(6)

,QQDWHLPPXQHUHVSRQVHWRSDWKRJHQLF

/HSWRVSLUD



9LUXOHQFHDVVD\E\LQIHFWLRQRIJXLQHDSLJV

7KHYLUXOHQFHRIOHSWRVSLUDOVWUDLQVZDVGHWHUPLQHGE\LQMHFWLRQRIJXLQHDSLJVZLWK

/HSWRVSLUD7KH SRVLWLYH FRQWURO ZDV DQ LVRODWH RI /HSWRVSLUD LQWHUURJDQV VHURYDU

&RSHQKDJHQLGHVLJQDWHG5-REWDLQHGIURPDSDWLHQWVXIIHULQJIURPDVHYHUH SXOPRQDU\ IRUP RI OHSWRVSLURVLV   /RZ LQ YLWUR SDVVDJHV RI WKLV LVRODWH ZHUH SDVVHGWKURXJKJXLQHDSLJVDQGUDWVWRPDLQWDLQYLUXOHQFH  

7KHVDSURSK\WH/ELÁH[DVHURYDU3DWRFVWUDLQ3DWRF,ZDVXVHGDVQHJDWLYHFRQWURO +DUWOH\PDOHJXLQHDSLJV &KDUOHV5LYHU/DERUDWRULHV8. DWZHHNVRIDJHZHLJKLQJ

WRJZHUHLQMHFWHGLQWUDSHULWRQHDOZLWKLQYLWURFXOWLYDWHG/HSWRVSLUDLQ

D ÀQDO YROXPH RI  õO PHGLD$QLPDOV ZHUH PRQLWRUHG GDLO\ IRU VLJQV RI LOOQHVV LQFOXGLQJZHLJKWORVVDQGORVVRIPRELOLW\DQGZHUHHXWKDQL]HGZKHQWKH\DSSHDUHG PRULEXQG,IQRLOOQHVVGHYHORSHGWKH\ZHUHHXWKDQL]HGRQGD\RUSRVWLQIHFWLRQ /LYHU DQG NLGQH\V ZHUH FXOWXUHG WR GHWHFW WKH SUHVHQFH RI OHSWRVSLUHV$OO VWXG\ SURWRFROV ZHUH DSSURYHG E\ WKH 8QLYHUVLW\ &ROOHJH 'XEOLQ$QLPDO 5HVHDUFK (WKLFV &RPPLWWHHDQGFRQGXFWHGXQGHUOLFHQVHIURPWKH'HSDUWPHQWRI+HDOWKDQG&KLOGUHQ

9LUXOHQFHWHVWLQJE\GHWHFWLRQRI/LJ$

7RWHVWYLUXOHQFHRIWKH/HSWRVSLUDZHSHUIRUPHGD/LJ$:HVWHUQEORW2QO\IUHVK SDWKRJHQLF LVRODWHV H[SUHVV WKLV SURWHLQ   5DEELW DQWL/LJ$ ZDV UDLVHG DJDLQVW DIUDJPHQWFDOOHG/LJ$1,DQGLQFOXGHVDPLQRDFLGV²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‰PHUFDSWRHWKDQRODQGEURPRSKHQROEOXHDQGWKHQERLOHGDW&IRU PLQXWHVDQGWKHHQVXLQJPL[WXUHWKHQORDGHGWRVWDFNLQJJHODQGHOHFWURSKRUHVHGDW 9FRQVWDQW)ROORZLQJHOHFWURSKRUHVLVWKHVHSDUDWHGSURWHLQVZHUHWUDQVIHUUHG WR D QLWURFHOOXORVH PHPEUDQH XVLQJ WKH %,25$' 0LQL 3URWHDQ ,,, DSSDUDWXV 7KH

(7)

&KDSWHU



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ÀHGWKHQDFRPSDULVRQZDVSHUIRUPHG,QWHUSUHWDWLRQRI UHVXOWVZDVE\YLVXDODQDO\VLVRIWKHEORW 7+3PRQRF\WHV 7KH7+3PRQRF\WHFHOOOLQHZDVREWDLQHGIURP$PHULFDQ7\SH&XOWXUH&ROOHFWLRQ $7&&7,% &HOOVZHUHFXOWXUHGLQ530,FRQWDLQLQJ)&6 ,QYLWURJHQ 3DLVOH\6FRWODQG8. P0JOXWDPLQ /RQ]D%DVHO6ZLW]HUODQG 8POSHQLFLOOLQ õJPOVWUHSWRP\FLQDQGõJPODPSKRWHULFLQ% ,QYLWURJHQ3DLVOH\6FRWODQG8.  DQGLQFXEDWHGDWž&&2)RXUGD\VEHIRUHWKHH[SHULPHQWFHOOVZHUHZDVKHG ZLWK530,)&6P0JOXWDPLQPHGLXPZLWKRXWDQWLELRWLFVDQWLP\FRWLFVDQG VXEFXOWXUHGLQWKLVPHGLXP3ULRUWRWKHH[SHULPHQW7+3FHOOVZHUHVSXQGRZQ DQGUHVXVSHQGHGLQIUHVK530,)&6P0JOXWDPLQWRDSSUR[LPDWHO\; FHOOVSHUPO)RUH[SHULPHQWVZLWKQRUPDOKXPDQVHUXP 1+6 ÀOWUDWHGKHDW LQDFWLYDWHG1+6 6DQTXLQ$PVWHUGDPWKH1HWKHUODQGV ZDVDGGHGWRWKHPHGLXP WRDÀQDOFRQFHQWUDWLRQRI 3%0&

+HSDULQL]HG EORRG ZDV FROOHFWHG DVHSWLFDOO\ IURP PXOWLSOH KHDOWK\ GRQRUV DQG 3%0& ZHUH REWDLQHG XVLQJ /\PSKRSUHSŒ $[LV6KLHOG 2VOR 1RUZD\  DFFRUGLQJ WR WKH PDQXIDFWXUHU·V JXLGHOLQHV %ULHÁ\ EORRG ZDV GLOXWHG  ZLWK S\URJHQ IUHH 1D&ODQGFDUHIXOO\OD\HUHGRQWRSRIWKH/\PSKRSUHSVROXWLRQDQGFHQWULIXJHG PLQXWHVDWJ7KHGLVWLQFWEDQGRI3%0&ZDVKDUYHVWHGZDVKHGZLWK530,DQG UHVXVSHQGHGLQ530,WRWKHVDPHYROXPHRIWKHRULJLQDOEORRG

(8)

,QQDWHLPPXQHUHVSRQVHWRSDWKRJHQLF /HSWRVSLUD  :KROH%ORRG 6KRUWO\EHIRUHVWDUWLQJWKHH[SHULPHQWKHSDULQL]HGEORRGZDVFROOHFWHGDVHSWLFDOO\ IURPPXOWLSOHKHDOWK\GRQRUV ([SHULPHQWV

([SHULPHQWV ZHUH SHUIRUPHG LQ TXDGUXSOLFDWH )LIW\ õO RI ZKROH EORRG RU FHOO VXVSHQVLRQVSUHSDUHGDVGHVFULEHGDERYHZHUHSXWLQWKHZHOOVRIDZHOOWLVVXH FXOWXUHSODWH *UHLQHU%LR2QH*PE+)ULFNHQKDXVHQ*HUPDQ\&(//67$5Š:HOO 3RO\VW\UHQH /HSWRVSLUDZHUHGLOXWHGLQ530,XQWLODSSURSULDWHFRQFHQWUDWLRQV

ZHUH UHDFKHG )LQDO FRQFHQWUDWLRQV UDQJHG IURP  ;  WR  ;  EDFWHULD

PO/HSWRVSLUDZHUHDGGHGWRWKHYDULRXVFHOOVXVSHQVLRQVWRDÀQDOYROXPHRI õOSHUZHOO&RQFHQWUDWLRQVRI3%0&ZHUHHTXLYDOHQWWRõOZKROHEORRGSHUZHOO

DSSUR[LPDWHO\;POPRQRF\WHV 3ODWHVZHUHLQFXEDWHGIRUVL[KRXUVDW°&

&2$IWHULQFXEDWLRQSODWHVZHUHFHQWULIXJHGDQGVXSHUQDWDQWZDVFROOHFWHGDQG

VWRUHG DW °& EHIRUH IXUWKHU WHVWLQJ :KHQ VWXG\LQJ 7/5 HQJDJHPHQW VSHFLÀF EORFNLQJ PRQRFORQDO DQWLERGLHV WR KXPDQ 7/5 DQG 7/5 ,QYLYR*HQ 7RXORXVH )UDQFH DQWLK7/5,J$ DQG DQWLK7/5,J$  ZHUH XVHG $QWLERGLHV ZHUH GLOXWHG LQ530,WRDÀQDOFRQFHQWUDWLRQRIQJPODQGQJPOUHVSHFWLYHO\ &RQWUROH[SHULPHQWVZHUHGRQHXVLQJ/7$ /7$6DXUHXV DQG/36 (FROLXOWUDSXUH ERWK,QYLYR*HQ7RXORXVH)UDQFH NQRZQIRUWKHLUFDSDFLW\WRVLJQDOWKURXJK7/5RU 7/5UHVSHFWLYHO\%ORRGFHOOVDQGDQWLERGLHVZHUHLQFXEDWHGIRUPLQXWHVRQWKH PLFURSODWHVKDNHUEHIRUH/HSWRVSLUDZHUHDGGHG .LOOLQJDVVD\

7R HYDOXDWH WKH VHQVLWLYLW\ RI WKH GLIIHUHQW /HSWRVSLUD VWUDLQV WR NLOOLQJ E\ KRVW

IDFWRUVRUFHOOVZH LQFXEDWHG LQ TXDGUXSOLFDWH  ; /HSWRVSLUDPO RIDOOVL[

VWUDLQVZLWKZKROHEORRG3%0&7+3DQG1+6IURPDKHDOWK\GRQRU ZLWKRXW D NQRZQ KLVWRU\ RI OHSWRVSLUDO LQIHFWLRQ QRW KHDW LQDFWLYDWHG  IRU VL[ KRXUV DW

°&  &2 &RQFHQWUDWLRQV DQG ÀQDO YROXPHV ZHUH LGHQWLFDO WR WKH LQFXEDWLRQ

H[SHULPHQWVGHVFULEHGDERYH2IHYHU\VDPSOHõOZDVWUDQVIHUUHGLQWRõO(0-+ VXSSOHPHQWHGZLWKÁXRURXUDFLOWRDYRLGFRQWDPLQDWLRQ1XPEHUVRIYLDEOH EDFWHULDZHUHHVWLPDWHGE\VHULDOWHQIROGGLOXWLRQRIVDPSOHV*URZWKZDVFKHFNHG DIWHUZHHNVLQFXEDWLRQDWž&E\GDUNÀHOGPLFURVFRS\

(9)

&KDSWHU



71)αDVVD\

/HYHOV RI 71)α LQ FXOWXUH VXSHUQDWDQWV ZHUH GHWHUPLQHG E\ HQ]\PHOLQNHG LPPXQRVRUEHQW DVVD\ %LRVRXUFH (XURSH 6$ 1LYHOOHV %HOJLXP KXPDQ 71)α

&\WR6HWV70 DFFRUGLQJWRWKHLQVWUXFWLRQVRIWKHPDQXIDFWXUHU

9LUXOHQFHWHVWLQJRI/LQWHUURJDQVVWUDLQVE\LQIHFWLRQRIJXLQHDSLJV

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

5(68/76

(10)

,QQDWHLPPXQHUHVSRQVHWRSDWKRJHQLF /HSWRVSLUD  9LUXOHQFHWHVWLQJE\GHWHFWLRQRI/LJ$ &RQVLVWHQWZLWKWKHUHVXOWVIURPWKHYLUXOHQFHWHVWLQJLQJXLQHDSLJV:HVWHUQEORW DQDO\VLVVKRZHGWKDWWKHIUHVKLVRODWH/LQWHUURJDQVVHURYDU%DWDYLDHVWUDLQ.DULDGL 6DWXVWURQJO\H[SUHVVHG/LJ$ZKLOH/LJ$ZDVRQO\ZHDNO\GHWHFWDEOHLQWKHPRGHUDWHO\ LQ YLWUR SDVVDJHG VWUDLQ /DQJNDZL /LJ$ ZDV FRPSOHWHO\ DEVHQW LQ WKH VDSURSK\WLF VWUDLQ/HSWRVSLUDELÁH[DVHURYDU3DWRFVWUDLQ3DWRF, GDWDQRWVKRZQ 

)LJXUH$5HFRUGRIJXLQHDSLJZHLJKWV

+DUWOH\ PDOH JXLQHD SLJV  ZHHNV RI DJH  ZHUH LQMHFWHG LQWUDSHULWRQHDOO\ ZLWK  LQ YLWUR FXOWLYDWHG/HSWRVSLUD$OOJXLQHDSLJVZHUHEHWZHHQJRQWKHGD\RILQIHFWLRQ GD\  :HLJKWVZHUHUHFRUGHGGDLO\XQWLOHXWKDQDVLD VHURYDU&RSHQKDJHQVWUDLQ5- VHURYDU3DWRFVWUDLQ3DWRF, VHURYDU/DLVWUDLQ/DL VHURYDU%DWDYLDHVWUDLQ6ZDUW VHURYDU/DLW\SH/DQJNDZLVWUDLQ/DQJNDZL VHURYDU%DWDYLDHVWUDLQ.DULDGL6DWX                 GD\VSRVWLQIHFWLRQ JXL QH D SL J Z HL JKW  J

(11)

&KDSWHU  )LJXUH%/XQJ*URVVSDWKRORJ\RIIROORZLQJLQIHFWLRQZLWKYDULRXVVWUDLQVRV/HSWRVSLUD /XQJ*URVVSDWKRORJ\RIJXLQHDSLJVIROORZLQJLQIHFWLRQZLWK D VHURYDU&RSHQKDJHQLVWUDLQ 5- E VHURYDU3DWRFVWUDLQ3DWRF, F VHURYDU/DLVWUDLQ/DL G VHURYDU%DWDYLDHVWUDLQ 6ZDUW H VHURYDU/DLW\SH/DQJNDZLVWUDLQ/DQJNDZL I VHURYDU%DWDYLDHVWUDLQ.DULDGL6DWX :LWKFRXUWHV\$00RQDKDQ9HWHULQDU\6FLHQFHV&HQWUH6FKRRORI$JULFXOWXUH)RRG6FLHQFH 9HWHULQDU\0HGLFLQH&ROOHJHRI/LIH6FLHQFHV8QLYHUVLW\&ROOHJH'XEOLQ%HOÀHOG'XEOLQ ,UHODQG 

$

&

(

%

'

)

(12)

,QQDWHLPPXQHUHVSRQVHWRSDWKRJHQLF

/HSWRVSLUD



)LJXUH&&XOWXUHUHVXOWVRINLGQH\DQGOLYHUWLVVXHIURPJXLQHDSLJVSRVWPRUWHP

/HSWRVSLUD .LGQH\FXOWXUH /LYHUFXOWXUH VHURYDU&RSHQKDJHQLVWUDLQ5-   VHURYDU3DWRFVWUDLQ3DWRF,   VHURYDU/DLVWUDLQ/DL   VHURYDU%DWDYLDHVWUDLQ6ZDUW   VHURYDU/DLW\SH/DQJNDZLVWUDLQ/DQJNDZL   VHURYDU%DWDYLDHVWUDLQ.DULDGL6DWX   'LIIHUHQWLQQDWHLPPXQHUHVSRQVHWRKHDWNLOOHGDQGDOLYH/LQWHUURJDQV )RUPHUVWXGLHVLQYHVWLJDWLQJWKHLQQDWHLPPXQHUHVSRQVHHOLFLWHGE\/LQWHUURJDQV ZHUH IRFXVHG RQ WKH KHDWVWDEOH OLSRSRO\VDFFKDULGH PRLHW\ RI WKHVH EDFWHULD +RZHYHUVLQFHKRVWFHOOVHQFRXQWHUOLYLQJEDFWHULDGXULQJLQIHFWLRQZHFRPSDUHG WKHUHVSRQVHRIKXPDQPRQRF\WLFFHOOV 7+3FHOOOLQH WRKHDWNLOOHGDQGYLDEOH SUHSDUDWLRQVRIWKHUHIHUHQFHDQGIUHVKLVRODWHIURPVHURYDUV%DWDYLDDQG/DLVWUDLQV PHQWLRQHGDERYH,QÀ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ÀFDQWO\ HQKDQFHG SRWHQF\ WR VWLPXODWH 7+3  FHOOV ZKHQ FRPSDUHG WR WKH OLYLQJ DYLUXOHQW %DWDYLD UHIHUHQFH VWUDLQ DQG ERWK OLYLQJ/DLSUHSDUDWLRQV,WFDQEHFRQFOXGHGWKDWWKHPLQLPDOO\SDVVHGKLJKO\YLUXOHQW %DWDYLDVWUDLQORVWDODUJHSDUWRILWVSRWHQF\WRDFWLYDWHDQLQQDWHLPPXQHUHVSRQVH XSRQKHDWNLOOLQJDQGWKDWOLYLQJYLUXOHQW/LQWHUURJDQVPD\H[HUWDUHODWLYHSRWHQW VWLPXODWLQJHIIHFWRQKXPDQPRQRF\WHV

(13)

&KDSWHU  6LQFHWKH7+3FHOOOLQHLVQRWDOZD\VDQDSSURSULDWHPRGHOIRUKXPDQPRQRF\WHV ZHSHUIRUPHGVWLPXODWLRQVZLWKKXPDQPRQRQXFOHDUFHOOV 3%0&·V 7KHUHVSRQVH WROLYLQJ/HSWRVSLUDE\3%0&·VZDVPRUHYLJRURXVWRERWKDYLUXOHQWUHIHUHQFHVWUDLQV ZKHQFRPSDUHGWRWKHIUHVKO\LVRODWHGYLUXOHQWVHURYDUV,QWHUHVWLQJO\LQWKLV3%0& HPSOR\LQJ WHVW WKH DYLUXOHQW %DWDYLD UHIHUHQFH VWUDLQ ZDV PRVW SRWHQW ZKLOH WKLV VWUDLQ GLVSOD\HG HTXDO SRWHQF\ LQ 7+3 WULJJHULQJ DV ERWK /DL VWUDLQV WHVWHG HLWKHUKHDWNLOOHGRUDOLYH7KHDERYHLQGLFDWHVWKDWWKHUHODWLYHSRWHQF\WRWULJJHU LQQDWHLPPXQHUHVSRQVHVRIJHQHWLFDOO\LQGLVWLQJXLVKDEOHYLUXOHQWDQGDYLUXOHQW/ LQWHUURJDQVVWUDLQVLVODUJHO\GHSHQGHQWRQWKHZD\RIDSSOLFDWLRQ DOLYHRUKHDW NLOOHG DQGWKHFHOOW\SHXVHG )LJXUH$FWLYDWLRQRI7+3FHOOVZLWKKHDWNLOOHGDQGOLYH/HSWRVSLUD &HOOVZHUHVWLPXODWHGIRUKZLWKYDU\LQJFRQFHQWUDWLRQVRI/HSWRVSLUD71)α FRQFHQWUDWLRQV ZHUHPHDVXUHGIURPFHOOFXOWXUHVXSHUQDWDQWV'DWDUHSUHVHQWWKHPHDQYDOXHVRITXDGUXSOLFDWH H[SHULPHQWV(UURUEDUVUHSUHVHQWWKHVWDQGDUGGHYLDWLRQ 6' RIWKHPHDQ/HIWSDQHO+HDW NLOOHG/HSWRVSLUD5LJKWSDQHO$OLYH/HSWRVSLUD             [ /HSWRVSLUDPO 71 )DDDD  SJ PO             [ /HSWRVSLUDPO 71 )DDDD  SJ PO 5HIHUHQFHVWUDLQ VHURYDU%DWDYLDH )UHVKLVRODWH VHURYDU%DWDYLDH )UHVKLVRODWH VHURYDU/DL 5HIHUHQFHVWUDLQ VHURYDU/DL 

(14)

,QQDWHLPPXQHUHVSRQVHWRSDWKRJHQLF /HSWRVSLUD  )LJXUH$FWLYDWLRQRI30%&ZLWKOLYH/HSWRVSLUD &HOOVZHUHVWLPXODWHGIRUKZLWKYDU\LQJFRQFHQWUDWLRQVRI/HSWRVSLUD71)α FRQFHQWUDWLRQV ZHUHPHDVXUHGIURPFHOOFXOWXUHVXSHUQDWDQWV'DWDUHSUHVHQWWKHPHDQYDOXHVRITXDGUXSOLFDWH H[SHULPHQWV(UURUEDUVUHSUHVHQWWKHVWDQGDUGGHYLDWLRQ 6' RIWKHPHDQ $EEUHYLDWLRQV3%0&SHULSKHUDOEORRGPRQRQXFOHDUFHOOV :KROHEORRG

'XULQJ WKH SDWKRSK\VLRORJ\ RI OHSWRVSLURVLV WKH /HSWRVSLUD HQFRXQWHU DQG VSUHDG WKURXJK WKH EORRG VWUHDP 7R H[SORUH WKH SURLQÁ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À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

(15)

&KDSWHU



/HSWRVSLUD7KH DSSDUHQW QRQDGGLWLYH VLJQDOLQJ EHKDYLRU RI7/5 DQG 7/5 XSRQ

LQFXEDWLRQZLWKWKHYLUXOHQWVWUDLQVXJJHVWVWKDWWKHVHUHFHSWRUVUHDFWLQV\QHUJLVP WRYLUXOHQW/HSWRVSLUDLQWKLVZKROHEORRGPRGH

)LJXUH$FWLYDWLRQRIZKROHEORRGZLWKOLYH/HSWRVSLUD

:KROH EORRG ZDV VWLPXODWHG IRU  K ZLWK YDU\LQJ FRQFHQWUDWLRQV RI /HSWRVSLUD 71)α FRQFHQWUDWLRQVZHUHPHDVXUHGIURPFHOOFXOWXUHVXSHUQDWDQWV'DWDUHSUHVHQWWKHPHDQYDOXHV RITXDGUXSOLFDWHH[SHULPHQWV(UURUEDUVUHSUHVHQWWKHVWDQGDUGGHYLDWLRQ 6' RIWKHPHDQ

)LJXUH7/5DQG7/5PHGLDWHDFWLYDWLRQRIZKROHEORRGLQUHVSRQVHWROLYH/HSWRVSLUD :KROHEORRGZDVVWLPXODWHGZLWK ; POOHSWRVSLUHVRIUHIHUHQFHVWUDLQVHURYDU%DWDYLDH RU ; PORIWKHHTXLYDOHQWIUHVKLVRODWHRIVHURYDU%DWDYLDHRU ; POLQWKH SUHVHQFHRIDQWL7/5DQGDQWL7/5DQWLERGLHV71)αZDVPHDVXUHGLQTXDGUXSOLFDWH(UURU EDUVUHSUHVHQWWKHVWDQGDUGGHYLDWLRQ 6' RIWKHPHDQ        5HIHUHQFHVWUDLQ VHURYDU%DWDYLDH )UHVKLVRODWH VHURYDU%DWDYLDH 5HIHUHQFHVWUDLQ VHURYDU/DL )UHVKLVRODWH VHURYDU/DL     [ /HSWRVSLUDPO 71) DDDD  S JP O 5HIHUHQFHVWUDLQ VHURYDU%DWDYLDH &RQW URO AD7/5D7/5 D7/5      71) DDDD  S JP O )UHVKLVRODWH VHURYDU%DWDYLDH &RQWUR O AD7/5D7/5 D7/5      71) DDDD  S JP O

(16)

,QQDWHLPPXQHUHVSRQVHWRSDWKRJHQLF /HSWRVSLUD  .LOOLQJRIWKHGLIIHUHQW/HSWRVSLUDVWUDLQVE\KRVWIDFWRUV ,QZKROHEORRGWKHYLUXOHQW/HSWRVSLUDVHHPHGPRUHSRWHQWLQLQLWLDWLQJDQLPPXQH UHVSRQVHWKDQWKHDYLUXOHQW/HSWRVSLUDDWOHDVWDWORZEDFWHULDOORDG7KHRSSRVLWH ZDVREVHUYHGLQUHDFWLRQVZLWKLVRODWHG3%0&·VZKLFKZHUHPRUHUHVSRQVLYHWRWKH DYLUXOHQW /HSWRVSLUD ,W DSSHDUHG WKDW WKH ZD\ RI H[SRVXUH RI /HSWRVSLUD WR WKH 71)SURGXFLQJPRQRF\WHVLVGLIIHUHQWLQZKROHEORRGFRPSDUHGWRWKHH[SRVXUHRI

/HSWRVSLUDWRPRQRF\WHVLQDSXULÀHGPRQRQXFOHDUFHOOIUDFWLRQRIEORRG2IFRXUVH

WKHLQWHJULW\DQGYLDELOLW\RIWKHGLIIHUHQW/HSWRVSLUDVWUDLQVPD\EHGLIIHUHQWLDOO\ DOWHUHG E\ HLWKHU SODVPD SURWHLQV RU FHOOXODU UHDFWLRQV 7KLV SURPSWHG XV WR WHVW SRWHQWLDONLOOLQJRIWKH/HSWRVSLUDVWUDLQVE\WKHGLIIHUHQWFHOOW\SHVFRPSOHPHQW RUZKROHEORRG7KXVWKHYLDELOLW\RIWKHGLIIHUHQW/HSWRVSLUDVWUDLQVZDVHYDOXDWHG VHPLTXDQWLWDWLYHO\E\FXOWXUHRIVHULDOGLOXWLRQVRI/HSWRVSLUDLQFXEDWHGZLWKWKH GLIIHUHQWFHOOVRUEORRGFRPSRQHQWV $VVKRZQLQÀJXUHLQFXEDWLRQVZLWK7+3FHOOVRU3%0&·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ÀFLHQWO\ DQG UDSLGO\ GHVWUR\HG E\ FRPSOHPHQW DFWLYLW\ZKLOHWKHYLUXOHQWPLQLPDOO\SDVVHG/HSWRVSLUDVWUDLQVHYDGHFRPSOHPHQW GHSHQGHQWNLOOLQJDQGDOVRGRQRWORRVHWKHLULQWHJULW\LQZKROHEORRG

(17)

&KDSWHU



)LJXUH.LOOLQJRI/HSWRVSLUD

/HSWRVSLUDDUHLQFXEDWHGIRUKRXUVIROGVHULDOGLOXWLRQVZHUHPDGHDIWHUKLQ(0-+DQG

OHSWRVSLUDOJURZWKZDVHYDOXDWHGDIWHUZHHNVLQFXEDWLRQDWƒ&

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

(18)

,QQDWHLPPXQHUHVSRQVHWRSDWKRJHQLF

/HSWRVSLUD

 /HSWRVSLURVLV FDQ FDXVH VHYHUH KXPDQ GLVHDVH OHDGLQJ WR EOHHGLQJ PXOWLRUJDQ

IDLOXUHDQGVHSWLFVKRFN7KHGLVHDVHLVFDXVHGE\VWUDLQVRIWKH/HSWRVSLUDLQWHUURJDQV EDFWHULDWKDWPD\GLIIHULQWKHLU/36PRLHW\ZKLFKLVXVHGWRGLVFULPLQDWHWKHGLIIHUHQW

/HSWRVSLUDVHURYDUV  3UHYLRXVUHSRUWVLGHQWLÀHG7/5LVWKHLQQDWHUHFHSWRUWKDW

UHFRJQL]HV /LQWHUURJDQV GHULYHG /36 DV ZHOO DV KHDWNLOOHG ZKROH / LQWHUURJDQV EDFWHULD  )XUWKHUPRUHWKH/36IURPYLUXOHQW/HSWRVSLUDZDVIRXQGWREHD ZHDNHUDFWLYDWRURIPRQRF\WHVWKDQWKH/36IURPDYLUXOHQW/HSWRVSLUD  7KHVH ÀQGLQJVVXJJHVWHGWKDW7/5LVQRWLQYROYHGLQWKHKRVWUHVSRQVHWR/LQWHUURJDQV DQGDSRWHQWLDOHVFDSHPHFKDQLVPRIYLUXOHQWEDFWHULDE\FRQFHDOPHQWRIWKH7/5 DFWLYDWLQJ/36VWUXFWXUH,QRUGHUWRIXUWKHUHOXFLGDWHKRZWKHLQQDWHLPPXQHV\VWHP UHDFWVWR/LQWHUURJDQVZHFRQÀ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

',6&866,21

(19)

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·V  H[SRVHG RQ WKHLU LQWDFW VXUIDFH 6LQFH LQGXFWLRQ RI VLJQDOLQJE\KXPDQ7/5WKURXJK3$03·VH[SRVHGE\/LQWHUURJDQVLVXQOLNHO\   WKHREVHUYHG7/5LQYROYHPHQWLVPRUHOLNHO\FDXVHGE\7/5DFWLYDWLQJUHOHDVHG GDQJHUDVVRFLDWHGPROHFXODUSDWWHUQV '$03·V E\KRVWFHOOVXSRQHQFRXQWHURIOLYLQJ VSHFLPHQRIWKLVLQYDVLYHJHQXVRIEDFWHULD   7RWKHEHVWRIRXUNQRZOHGJHZHDUHWKHÀ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

%DVLFDOO\ KXPDQ ZKROH EORRG LQFXEDWLRQV ZLWK YLDEOH /HSWRVSLUD UHYHDOHG WKDW YLUXOHQFHFKDUDFWHULVWLFVRI/LQWHUURJDQVDUHDVVRFLDWHGZLWKFRPSOHWHUHVLVWDQFH WRNLOOLQJE\QRUPDOZKROHEORRGDQGQRWZLWKLPSDLUHGUHFRJQLWLRQE\WKHFHOOXODU UHFHSWRUVRIWKHLQQDWHLPPXQHV\VWHP

2XUUHVXOWVDUHLQOLQHZLWKSUHYLRXVZRUNVKRZLQJWKDWSDWKRJHQLF/HSWRVSLUDDUH DEOHWRVXUYLYHLQWKHQRQLPPXQHKRVWE\HYDGLQJWRYDULRXVGHJUHHFRPSOHPHQW

(20)

,QQDWHLPPXQHUHVSRQVHWRSDWKRJHQLF

/HSWRVSLUD

 PHGLDWHG NLOOLQJ   $OWKRXJK & LV SUREDEO\ HTXDOO\ GHSRVLWHG RQ ERWK QRQ

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ÀQGLQJV   VXJJHVWLQJWKDWSKDJRF\WRVLVRUWKHUHOHDVHRIEDFWHULFLGDOPHGLDWRUVDUHQRWPDMRU SURFHVVHVLQYROYHGLQWKHNLOOLQJRI/HSWRVSLUD

1DOO\ HW DO   IRXQG LQ D OHWKDO JXLQHD SLJ PRGHO WKDW LQ KRVW WLVVXH GHULYHG OHSWRVSLUHV WKH /36 2DQWLJHQ FRQWHQW ZDV PDUNHGO\ UHGXFHG FRPSDUHG ZLWK LQ YLWUR FXOWXUHG OHSWRVSLUHV +RZHYHU KRVW WLVVXH GHULYHG OHSWRVSLUHV LVRODWHG IURP FKURQLFDOO\LQIHFWHGUDWNLGQH\WXEXOHVZHUHLQGLVWLQJXLVKDEOHIURPLQYLWURFXOWXUHG OHSWRVSLUHV,WZDVVKRZQWKDWWKHVXUIDFHH[SUHVVHGOLSRSURWHLQ/LJ%RQO\SUHVHQW LQSDWKRJHQLFVSHFLHV  ZDVDWWHQXDWHGGXULQJFXOWXUHSDVVDJH  7KHH[DFW IXQFWLRQDOFRQVHTXHQFHRI/LJ%GHÀFLHQF\RI/HSWRVSLUDLVQRW\HWHOXFLGDWHG 7KHDELOLW\RISKDJRF\WHVWRNLOOSDWKRJHQLF/HSWRVSLUDGHSHQGVRQRSVRQLVDWLRQZLWK VSHFLÀFLPPXQHVHUXP  ,QWKHDEVHQFHRILPPXQHVHUXPSDWKRJHQLF/HSWRVSLUD PD\ LQWHUDFW EXW DUH QRW LQJHVWHG RU NLOOHG E\ PRQRF\WHV PDFURSKDJHV DQG QHXWURSKLOV7KXVLWDSSHDUVWKDWLQWKHQRQLPPXQHSDWLHQWSDWKRJHQLF/HSWRVSLUD DUHQRWHIIHFWLYHO\NLOOHGE\WKHLQQDWHLPPXQHV\VWHPXSRQHQWU\YLDVNLQRUPXFRVD DEUDVLRQV:KHQOLYLQJ/LQWHUURJDQVHQWHUVWKHFLUFXODWLRQZHVKRZKHUHWKDWKXPDQ EORRG FHOOV PD\ UHDFW LQ D ZD\ WKDW OHDGV WR7/5 DQG7/5 GHSHQGHQW F\WRNLQH SURGXFWLRQE\V\QHUJLVWLFDFWLRQVRIWKHVHUHFHSWRUV

&OHDUO\ WKHUH DUH IXQGDPHQWDO GLIIHUHQFHV EHWZHHQ IUHVK FOLQLFDO / LQWHUURJDQV LVRODWHV DQG LVRODWHV ZKLFK KDYH EHHQ PDLQWDLQHG IRU D ORQJ WLPH LQ YLWUR 7KH GDWDSUHVHQWHGKHUHLQHPSKDVL]HWKHLPSRUWDQFHWRXVHYLDEOHORZSDVVDJHFOLQLFDO LVRODWHVWRVWXG\WKHKRVWUHVSRQVHWR/LQWHUURJDQVLQIHFWLRQ,QFRQFOXVLRQRXU UHVXOWV VKRZ WKDW WKH LQQDWH KXPDQ KRVW UHVSRQVH WR OHSWRVSLUDHPLD PD\ LQYROYH

(21)

&KDSWHU  V\QHUJLVWLFDFWLRQVRI7/5DQG7/57KHVHVWXGLHVSURPSWIXUWKHUUHVHDUFKWRWKH PHFKDQLVPRIDFWLRQRIWKLVREVHUYHGV\QHUJ\DQGVWXGLHVWRXQUDYHOZKHWKHU7/5LV LQYROYHGGXULQJKXPDQOHSWRVSLURVLV   $FNQRZOHGJPHQWV :HZRXOGOLNHWRWKDQN3UHFLRXV(0DQ\HQJDIRUVHWWLQJXSWKH/LJ$H[SHULPHQWV

(22)

,QQDWHLPPXQHUHVSRQVHWRSDWKRJHQLF

/HSWRVSLUD



  $QGHUVRQ'/DQG5&-RKQVRQ(OHFWURQPLFURVFRS\RILPPXQHGLVUXSWLRQ RIOHSWRVSLUHVDFWLRQRIFRPSOHPHQWDQGO\VR]\PH-%DFWHULRO   $UHDQ 9 0  7KH SDWKRORJLF DQDWRP\ DQG SDWKRJHQHVLV RI IDWDO KXPDQ

OHSWRVSLURVLV :HLO·VGLVHDVH $P-3DWKRO   %KDUWL$5-(1DOO\-15LFDOGL0$0DWWKLDV00'LD]0$/RYHWW31 /HYHWW5+*LOPDQ05:LOOLJ(*RWX]]RDQG-09LQHW]/HSWRVSLURVLV D]RRQRWLFGLVHDVHRIJOREDOLPSRUWDQFH/DQFHW,QIHFW'LV   &KLHUDNXO:)0GH<6XSXWWDPRQJNRO5/LPSDLERRQ$'RQGRUS1-:KLWH DQG7YDQGHU3ROO'LIIHUHQWLDOH[SUHVVLRQRILQWHUIHURQJDPPDDQGLQWHUIHURQ JDPPDLQGXFLQJF\WRNLQHVLQ7KDLSDWLHQWVZLWKVFUXEW\SKXVRUOHSWRVSLURVLV&OLQ ,PPXQRO

  &LQFR 0 DQG ( %DQÀ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ÀFDWLRQRIWKH6SHFLHV/HSWRVSLUD,QWHUURJDQV DQG+LVWRU\RILWV6HURYDUV*URQLQJHQ8QLYHUVLW\3UHVV*URQLQJHQ

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

5()(5(1&(6

(23)

&KDSWHU



  0HULHQ)'3RUWQRL3%RXUK\)&KDUDYD\$%HUOLR]$UWKDXGDQG*%DUDQWRQ $ UDSLG DQG TXDQWLWDWLYH PHWKRG IRU WKH GHWHFWLRQ RI /HSWRVSLUD VSHFLHV LQ KXPDQOHSWRVSLURVLV)(060LFURELRO/HWW   1DKRUL0$()RXUQLH$PD]RX]164XH*HZLUWK9%DOOR\0&KLJQDUG&5 5DHW]*6DLQW,DQG&:HUWV'LIIHUHQWLDO7/5UHFRJQLWLRQRIOHSWRVSLUDOOLSLG $DQGOLSRSRO\VDFFKDULGHLQPXULQHDQGKXPDQFHOOV-,PPXQRO   1DOO\-(&&KDQWUDQXZDW;<:X0&)LVKEHLQ003HUHLUD--'D6LOYD '5%ODQFRDQG0$/RYHWW$OYHRODUVHSWDOGHSRVLWLRQRILPPXQRJOREXOLQ DQGFRPSOHPHQWSDUDOOHOVSXOPRQDU\KHPRUUKDJHLQDJXLQHDSLJPRGHORIVHYHUH SXOPRQDU\OHSWRVSLURVLV$P-3DWKRO   1DOO\-((&KRZ0&)LVKEHLQ'5%ODQFRDQG0$/RYHWW&KDQJHVLQ OLSRSRO\VDFFKDULGH2DQWLJHQGLVWLQJXLVKDFXWHYHUVXVFKURQLF/HSWRVSLUDLQWHUURJDQV LQIHFWLRQV,QIHFW,PPXQ   3DODQLDSSDQ58<)&KDQJ66-XVXI6$UWLXVKLQ-)7LPRQH\630F'RQRXJK 6&%DUU7-'LYHUV.:6LPSVRQ3/0F'RQRXJKDQG+20RKDPPHG &ORQLQJDQGPROHFXODUFKDUDFWHUL]DWLRQRIDQLPPXQRJHQLF/LJ$SURWHLQRI/HSWRVSLUD LQWHUURJDQV,QIHFW,PPXQ

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

  :DJHQDDU - ) 3 - GH 9ULHV DQG 5 $ +DUWVNHHUO  /HSWRVSLURVLV ZLWK SXOPRQDU\KHPRUUKDJHFDXVHGE\DQHZVWUDLQRIVHURYDU/DL/DQJNDZL-7UDYHO 0HG

  :DQJ % - 6XOOLYDQ * : 6XOOLYDQ DQG * / 0DQGHOO  ,QWHUDFWLRQ RI OHSWRVSLUHVZLWKKXPDQSRO\PRUSKRQXFOHDUQHXWURSKLOV,QIHFW,PPXQ   :DQJ%-$6XOOLYDQ*:6XOOLYDQDQG*/0DQGHOO5ROHRIVSHFLÀF DQWLERG\LQLQWHUDFWLRQRIOHSWRVSLUHVZLWKKXPDQPRQRF\WHVDQGPRQRF\WHGHULYHG PDFURSKDJHV,QIHFW,PPXQ   :HUWV&5,7DSSLQJ-&0DWKLVRQ7+&KXDQJ9.UDYFKHQNR*6DLQW,' $+DDNH3-*RGRZVNL)+D\DVKL$2]LQVN\'08QGHUKLOO&-.LUVFKQLQJ+ :DJQHU$$GHUHP367RELDVDQG5-8OHYLWFK/HSWRVSLUDOOLSRSRO\VDFFKDULGH DFWLYDWHVFHOOVWKURXJKD7/5GHSHQGHQWPHFKDQLVP1DW,PPXQRO

(24)

,QQDWHLPPXQHUHVSRQVHWRSDWKRJHQLF

/HSWRVSLUD

(25)
(26)

,,,

3$57

'LDJQRVWLFDQGHSLGHPLRORJLFDODVSHFWV

(27)

Referenties

GERELATEERDE DOCUMENTEN

Every architectural encounter will then become an experience in which we can rely on our senses and, moreover, a sensation of sublimity that is precluded by any form

It is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), other than for strictly

Zeer duidelijk is de relatie te zien tussen de schooltijden en het aantal slachtoffers: grote aantallen slachtoffers op tijden dat de scholieren van of naar

EORRG SUHVVXUH DQG FUHDWLQLQH FOHDUDQFH DW WKH DJH RI  \HDUV XS WR WKH DJH RI.  \HDUV &amp;KDSWHU IRXU GHVFULEHV WKH DVVRFLDWLRQ EHWZHHQ EORRG

Subsequently, the location of the aerial vehicle (AV) is estimated using another KF with the multilateration (MLAT) method and the dynamic model of the AV.. We demonstrate

The complex scal- ing of the length of BSS waves with their flow depth, the segregation rate and other flow pa- rameters, forced us to use a large particle-size ratio and a shallow

4XDOLW\ RI WKH WULSOLFDWHV DQG GLVWULEXWLRQ RI WKH GDWD ZDV DVVHVVHG DQG. TXDQWLOHQRUPDOLVDWLRQ