%PDF-1.6
%
1 0 obj
<>
endobj
2 0 obj
<>stream
Valérie Fontaine, Elodie Monteiro, Elena Brazhnikova, Laëtitia Lesage, Christine Balducci, Louis Guibout, Laurence Feraille, Pierre-Paul Elena, José-Alain Sahel, Stanislas Veillet, René Lafont
Norbixin Protects Retinal Pigmented Epithelium Cells and Photoreceptors against A2E-Mediated Phototoxicity In Vitro and In Vivo
www.plosone.org
www.plosone.org
endstream
endobj
3 0 obj
<>/XObject<>>>/CropBox[0 0 612 792]/MediaBox[0 0 612 792]/Parent 12 0 R/Annots 13 0 R/Contents 14 0 R/TrimBox[0 0 612 792]>>
endobj
13 0 obj
[15 0 R 16 0 R 17 0 R 18 0 R 19 0 R 20 0 R 21 0 R 22 0 R 23 0 R 24 0 R 25 0 R 26 0 R 27 0 R 28 0 R 29 0 R 30 0 R 31 0 R 32 0 R 33 0 R 34 0 R 35 0 R 36 0 R 37 0 R 38 0 R 39 0 R 40 0 R 41 0 R 42 0 R 43 0 R 44 0 R 45 0 R 46 0 R 47 0 R 48 0 R 49 0 R 50 0 R 51 0 R 52 0 R 53 0 R 54 0 R 55 0 R 56 0 R 57 0 R 58 0 R 59 0 R 60 0 R 61 0 R 62 0 R 63 0 R 64 0 R 65 0 R 66 0 R 67 0 R 68 0 R]
endobj
15 0 obj
<>/Border[0 0 0]/Dest(Rpone.0167793.ref003)>>
endobj
16 0 obj
<>/Border[0 0 0]/Dest(Rpone.0167793.ref004)>>
endobj
17 0 obj
<>/Border[0 0 0]/Dest(Rpone.0167793.ref003)>>
endobj
18 0 obj
<>/Border[0 0 0]/Dest(Rpone.0167793.ref005)>>
endobj
19 0 obj
<>/Border[0 0 0]/Dest(Rpone.0167793.ref006)>>
endobj
20 0 obj
<>/Border[0 0 0]/Dest(Rpone.0167793.ref007)>>
endobj
21 0 obj
<>/Border[0 0 0]/Dest(Rpone.0167793.ref008)>>
endobj
22 0 obj
<>/Border[0 0 0]/Dest(Rpone.0167793.ref008)>>
endobj
23 0 obj
<>/Border[0 0 0]/Dest(Rpone.0167793.ref009)>>
endobj
24 0 obj
<>/Border[0 0 0]/Dest(Rpone.0167793.ref010)>>
endobj
25 0 obj
<>/Border[0 0 0]/Dest(Rpone.0167793.ref007)>>
endobj
26 0 obj
<>/Border[0 0 0]/Dest(Rpone.0167793.ref011)>>
endobj
27 0 obj
<>/Border[0 0 0]/Dest(Rpone.0167793.ref012)>>
endobj
28 0 obj
<>/Border[0 0 0]/Dest(Rpone.0167793.ref013)>>
endobj
29 0 obj
<>/Border[0 0 0]/Dest(Rpone.0167793.ref014)>>
endobj
30 0 obj
<>/Border[0 0 0]/Dest(Rpone.0167793.ref015)>>
endobj
31 0 obj
<>/Border[0 0 0]/Dest(Rpone.0167793.ref016)>>
endobj
32 0 obj
<>/Border[0 0 0]/Dest(Rpone.0167793.ref017)>>
endobj
33 0 obj
<>/Border[0 0 0]/Dest(Rpone.0167793.ref018)>>
endobj
34 0 obj
<>/Border[0 0 0]/Dest(Rpone.0167793.ref019)>>
endobj
35 0 obj
<>/Border[0 0 0]/Dest(Rpone.0167793.ref020)>>
endobj
36 0 obj
<>/Border[0 0 0]/Dest(Rpone.0167793.ref021)>>
endobj
37 0 obj
<>/Border[0 0 0]/Dest(Rpone.0167793.ref022)>>
endobj
38 0 obj
<>/Border[0 0 0]/Dest(Rpone.0167793.ref023)>>
endobj
39 0 obj
<>/Border[0 0 0]/Dest(Rpone.0167793.ref024)>>
endobj
40 0 obj
<>/Border[0 0 0]/Dest(Rpone.0167793.ref025)>>
endobj
41 0 obj
<>/Border[0 0 0]/Dest(Rpone.0167793.ref026)>>
endobj
42 0 obj
<>/Border[0 0 0]/Dest(Rpone.0167793.ref027)>>
endobj
43 0 obj
<>/Border[0 0 0]/Dest(Rpone.0167793.ref028)>>
endobj
44 0 obj
<>/Border[0 0 0]/Dest(Rpone.0167793.ref029)>>
endobj
45 0 obj
<>/Border[0 0 0]/Dest(Rpone.0167793.ref030)>>
endobj
46 0 obj
<>/Border[0 0 0]/Dest(Rpone.0167793.ref031)>>
endobj
47 0 obj
<>/Border[0 0 0]/Dest(Rpone.0167793.ref032)>>
endobj
48 0 obj
<>/Border[0 0 0]/Dest(Rpone.0167793.ref033)>>
endobj
49 0 obj
<>/Border[0 0 0]/Dest(Rpone.0167793.ref034)>>
endobj
50 0 obj
<>/Border[0 0 0]/Dest(Rpone.0167793.ref035)>>
endobj
51 0 obj
<>/Border[0 0 0]/Dest(Rpone.0167793.ref036)>>
endobj
52 0 obj
<>/Border[0 0 0]/Dest(Rpone.0167793.ref037)>>
endobj
53 0 obj
<>/Border[0 0 0]/Dest(Rpone.0167793.ref038)>>
endobj
54 0 obj
<>/Border[0 0 0]/Dest(Rpone.0167793.ref039)>>
endobj
55 0 obj
<>/Border[0 0 0]/Dest(Rpone.0167793.ref040)>>
endobj
56 0 obj
<>/Border[0 0 0]/Dest(Rpone.0167793.ref041)>>
endobj
57 0 obj
<>/Border[0 0 0]/Dest(Rpone.0167793.ref042)>>
endobj
58 0 obj
<>/Border[0 0 0]/Dest(Rpone.0167793.ref043)>>
endobj
59 0 obj
<>/Border[0 0 0]/Dest(Rpone.0167793.ref044)>>
endobj
60 0 obj
<>/Border[0 0 0]/Dest(Rpone.0167793.ref045)>>
endobj
61 0 obj
<>/Border[0 0 0]/Dest(Rpone.0167793.ref046)>>
endobj
62 0 obj
<>/Border[0 0 0]/Dest(Rpone.0167793.ref047)>>
endobj
63 0 obj
<>/Border[0 0 0]/Dest(Rpone.0167793.ref048)>>
endobj
64 0 obj
<>/Border[0 0 0]/Dest(Rpone.0167793.ref049)>>
endobj
65 0 obj
<>/Border[0 0 0]/Dest(Rpone.0167793.ref050)>>
endobj
66 0 obj
<>/Border[0 0 0]/Dest(Rpone.0167793.ref036)>>
endobj
67 0 obj
<>/Border[0 0 0]/Dest(Rpone.0167793.g001)>>
endobj
68 0 obj
<>/Border[0 0 0]/Dest(Rpone.0167793.ref051)>>
endobj
14 0 obj
[69 0 R 70 0 R 71 0 R 72 0 R 73 0 R 74 0 R 75 0 R 76 0 R 77 0 R 78 0 R 79 0 R 80 0 R 81 0 R 82 0 R 83 0 R 84 0 R 85 0 R 86 0 R 87 0 R 88 0 R 89 0 R 90 0 R 91 0 R 92 0 R 93 0 R 94 0 R 95 0 R 96 0 R 97 0 R 98 0 R 99 0 R 100 0 R 101 0 R 102 0 R 103 0 R 104 0 R 105 0 R 106 0 R 107 0 R 108 0 R 109 0 R 110 0 R 111 0 R 112 0 R 113 0 R 114 0 R 115 0 R 116 0 R 117 0 R 118 0 R 119 0 R]
endobj
69 0 obj
<>stream
q
0.83 0.64 0.02 0 k
394.5827 680.315 m
399.2882 680.315 l
h
f*
401.5559 680.315 m
406.3181 680.315 l
h
f*
296.6173 654.3496 m
301.3795 654.3496 l
h
f*
227.0551 641.3102 m
231.8173 641.3102 l
h
f*
368.5606 641.3102 m
373.2661 641.3102 l
h
f*
375.5339 641.3102 m
380.2961 641.3102 l
h
f*
300.3024 628.3276 m
305.0079 628.3276 l
h
f*
447.3071 628.3276 m
452.0693 628.3276 l
h
f*
454.337 628.3276 m
459.0992 628.3276 l
h
f*
540.2268 615.3449 m
549.7512 615.3449 l
h
f*
496.3465 602.3055 m
501.1087 602.3055 l
h
f*
289.2472 576.3402 m
298.7717 576.3402 l
h
f*
301.0394 576.3402 m
310.5071 576.3402 l
h
f*
499.8047 576.3402 m
509.2724 576.3402 l
h
f*
511.5402 576.3402 m
521.0646 576.3402 l
h
f*
523.3323 576.3402 m
532.8 576.3402 l
h
f*
370.148 563.3008 m
379.6157 563.3008 l
h
f*
381.8835 563.3008 m
391.4079 563.3008 l
h
f*
393.6756 563.3008 m
403.1433 563.3008 l
h
f*
405.411 563.3008 m
414.9354 563.3008 l
h
f*
236.7496 537.3354 m
246.274 537.3354 l
h
f*
456.7181 537.3354 m
466.2425 537.3354 l
h
f*
255.9118 524.2961 m
265.3795 524.2961 l
h
f*
203.4142 498.3307 m
212.9386 498.3307 l
h
f*
427.9748 459.326 m
437.4992 459.326 l
h
f*
439.7102 459.326 m
449.2346 459.326 l
h
f*
451.5024 459.326 m
461.0268 459.326 l
h
f*
463.2378 459.326 m
472.7622 459.326 l
h
f*
475.0299 459.326 m
484.5543 459.326 l
h
f*
509.4992 427.3512 m
519.0236 427.3512 l
h
f*
403.9937 414.3118 m
413.5181 414.3118 l
h
f*
423.6094 401.3291 m
433.0772 401.3291 l
h
f*
476.1638 382.337 m
485.6882 382.337 l
h
f*
487.9559 382.337 m
497.4236 382.337 l
h
f*
338.3433 369.2976 m
347.811 369.2976 l
h
f*
350.0787 369.2976 m
359.6031 369.2976 l
h
f*
253.4173 337.3228 m
262.9417 337.3228 l
h
f*
265.1528 337.3228 m
274.6772 337.3228 l
h
f*
276.9449 337.3228 m
286.4693 337.3228 l
h
f*
449.0646 337.3228 m
458.589 337.3228 l
h
f*
215.4331 305.348 m
224.9008 305.348 l
h
f*
227.1685 305.348 m
236.6929 305.348 l
h
f*
491.1874 305.348 m
500.7118 305.348 l
h
f*
444.189 273.3165 m
453.6567 273.3165 l
h
f*
438.0661 189.2976 m
447.5906 189.2976 l
h
f*
449.8016 189.2976 m
459.326 189.2976 l
h
f*
411.6472 150.3496 m
421.1717 150.3496 l
h
f*
423.4394 150.3496 m
432.9638 150.3496 l
h
f*
281.4803 137.3102 m
291.0047 137.3102 l
h
f*
364.1953 137.3102 m
373.7197 137.3102 l
h
f*
544.3654 137.3102 m
553.8331 137.3102 l
h
f*
314.8157 124.3276 m
324.3402 124.3276 l
h
f*
240.3213 98.3055 m
259.8236 98.3055 l
h
f*
375.137 98.3055 m
384.6614 98.3055 l
h
f*
0 g
1 j
1 J
0 w
10 0 0 10 200.0125 707.4141 cm
BT
/F8 1 Tf
1 TL
-0.004 Tc
0 0 Td
(oxidized)Tj
3.6169 0 Td
(photoreceptor)Tj
5.9131 0 Td
(outer)Tj
2.347 0 Td
(segments.)Tj
4.1443 0 Td
(The)Tj
1.7858 0 Td
(A2E-induced)Tj
5.5445 0 Td
(disturbance)Tj
4.9096 0 Td
(of)Tj
1.0148 0 Td
(RPE)Tj
1.9729 0 Td
(cell)Tj
1.559 0 Td
(lysosomal)Tj
-32.8079 -1.3039 Td
(activity)Tj
3.118 0 Td
(supposedly)Tj
4.6602 0 Td
(represents)Tj
4.3199 0 Td
(one)Tj
1.7008 0 Td
(early)Tj
2.1487 0 Td
(stage)Tj
2.1996 0 Td
(of)Tj
1.0148 0 Td
(AMD)Tj
2.5342 0 Td
(development)Tj
5.4141 0 Td
(and)Tj
1.7292 0 Td
(correlates)Tj
4.0761 0 Td
(with)Tj
2.0013 0 Td
(the)Tj
-34.9169 -1.2982 Td
(accumulation)Tj
5.6749 0 Td
(of)Tj
1.0148 0 Td
(A2E)Tj
1.9502 0 Td
(and)Tj
1.7291 0 Td
(related)Tj
2.948 0 Td
(retinal)Tj
2.8063 0 Td
(dimers)Tj
2.9934 0 Td
([)Tj
0.83 0.64 0.02 0 k
(3)Tj
0 g
(,)Tj
0.83 0.64 0.02 0 k
(4)Tj
0 g
(].)Tj
-17.9205 -1.2983 Td
(A2E)Tj
1.9502 0 Td
(and)Tj
1.7291 0 Td
(its)Tj
1.1509 0 Td
(isomers)Tj
3.3278 0 Td
(are)Tj
1.4514 0 Td
(formed)Tj
3.1577 0 Td
(by)Tj
1.1792 0 Td
(the)Tj
1.4684 0 Td
(reaction)Tj
3.4922 0 Td
(of)Tj
1.0148 0 Td
(two)Tj
/F13 1 Tf
1.7121 0 Td
[()7()20()16()]TJ
/F8 1 Tf
(-retinal)Tj
5.1591 0 Td
(molecules)Tj
4.2009 0 Td
(with)Tj
1.9956 0 Td
(phos-)Tj
-34.1856 -1.2983 Td
(phatidyl-ethanolamine)Tj
9.3202 0 Td
([)Tj
0.83 0.64 0.02 0 k
(3)Tj
0 g
(].)Tj
1.5987 0 Td
(A2E)Tj
1.9503 0 Td
(is)Tj
0.8503 0 Td
(an)Tj
1.2019 0 Td
(amphiphilic)Tj
5.0343 0 Td
(molecule,)Tj
4.0649 0 Td
(which)Tj
2.6475 0 Td
(can)Tj
1.6271 0 Td
(alter)Tj
1.9956 0 Td
(membrane)Tj
4.5637 0 Td
(prop-)Tj
-34.8545 -1.3039 Td
(erties)Tj
2.364 0 Td
([)Tj
0.83 0.64 0.02 0 k
(5)Tj
0 g
(])Tj
1.3777 0 Td
(and)Tj
1.7291 0 Td
(impair)Tj
2.897 0 Td
(lysosomal)Tj
4.1555 0 Td
(functions)Tj
3.9912 0 Td
([)Tj
0.83 0.64 0.02 0 k
(6)Tj
0 g
(,)Tj
0.83 0.64 0.02 0 k
(7)Tj
0 g
(];)Tj
2.3017 0 Td
(A2E)Tj
1.9446 0 Td
(can)Tj
1.627 0 Td
(activate)Tj
3.2542 0 Td
(inflammatory)Tj
5.7089 0 Td
(processes)Tj
3.9685 0 Td
(by)Tj
-35.3194 -1.2982 Td
(recruiting)Tj
4.1839 0 Td
(macrophages)Tj
5.5048 0 Td
([)Tj
0.83 0.64 0.02 0 k
(8)Tj
0 g
(],)Tj
1.5987 0 Td
(increase)Tj
3.4753 0 Td
(VEGF)Tj
2.7269 0 Td
(secretion)Tj
/F13 1 Tf
3.8438 0 Td
[()12()]TJ
1.0148 0 Td
[()-13()14()7()20()]TJ
/F8 1 Tf
2.0409 0 Td
([)Tj
0.83 0.64 0.02 0 k
(8)Tj
0 g
(,)Tj
0.83 0.64 0.02 0 k
(9)Tj
0 g
(])Tj
2.0806 0 Td
(and)Tj
1.7291 0 Td
(possibly)Tj
3.4413 0 Td
(also)Tj
1.7688 0 Td
(promote)Tj
-33.4089 -1.2983 Td
(neovascularization)Tj
7.6875 0 Td
(through)Tj
3.4412 0 Td
(enhanced)Tj
4.0762 0 Td
(vascular)Tj
3.4752 0 Td
(endothelial)Tj
4.6715 0 Td
(growth)Tj
3.0728 0 Td
(factor)Tj
2.5398 0 Td
(production)Tj
4.7168 0 Td
([)Tj
0.83 0.64 0.02 0 k
(10)Tj
0 g
(].)Tj
-32.4848 -1.3039 Td
(High)Tj
2.2507 0 Td
(A2E)Tj
1.9502 0 Td
(concentrations)Tj
6.1795 0 Td
(increase)Tj
3.4696 0 Td
(oxidative)Tj
3.8664 0 Td
(stress)Tj
2.3981 0 Td
(in)Tj
1.0318 0 Td
(RPE)Tj
1.9729 0 Td
(cells)Tj
/F13 1 Tf
1.9219 0 Td
[()12()]TJ
1.0148 0 Td
[()-13()14()7()20()]TJ
/F8 1 Tf
2.0409 0 Td
([)Tj
0.83 0.64 0.02 0 k
(7)Tj
0 g
(].)Tj
1.6044 0 Td
(In)Tj
1.1055 0 Td
(the)Tj
1.474 0 Td
(presence)Tj
-33.4769 -1.2983 Td
(of)Tj
1.0147 0 Td
(blue)Tj
1.9219 0 Td
(light)Tj
2.0239 0 Td
(and)Tj
1.7348 0 Td
(oxygen,)Tj
3.3052 0 Td
(A2E)Tj
1.9502 0 Td
(undergoes)Tj
4.3767 0 Td
(photooxidation)Tj
6.4006 0 Td
(as)Tj
1.0148 0 Td
(evidenced)Tj
4.2406 0 Td
(by)Tj
1.1792 0 Td
(the)Tj
1.4683 0 Td
(appearance)Tj
4.7452 0 Td
(of)Tj
-35.3761 -1.2983 Td
(toxic)Tj
2.1769 0 Td
(oxygen)Tj
3.0841 0 Td
(adducts)Tj
3.3222 0 Td
([)Tj
0.83 0.64 0.02 0 k
(11)Tj
0 g
(,)Tj
0.83 0.64 0.02 0 k
(12)Tj
0 g
(].)Tj
3.2542 0 Td
(It)Tj
0.856 0 Td
(generates)Tj
3.9685 0 Td
(small)Tj
2.3301 0 Td
(amounts)Tj
3.7133 0 Td
(of)Tj
1.0148 0 Td
(singlet)Tj
2.8346 0 Td
(oxygen)Tj
3.0841 0 Td
([)Tj
0.83 0.64 0.02 0 k
(13)Tj
0 g
(,)Tj
0.83 0.64 0.02 0 k
(14)Tj
0 g
(,)Tj
0.83 0.64 0.02 0 k
(15)Tj
0 g
(])Tj
4.2009 0 Td
(and)Tj
1.7292 0 Td
(is)Tj
-35.5689 -1.3039 Td
(finally)Tj
2.7042 0 Td
(cleaved)Tj
3.1521 0 Td
(to)Tj
1.0261 0 Td
(small)Tj
2.3244 0 Td
(reactive)Tj
3.3165 0 Td
(aldehydes)Tj
4.1499 0 Td
([)Tj
0.83 0.64 0.02 0 k
(16)Tj
0 g
(,)Tj
0.83 0.64 0.02 0 k
(17)Tj
0 g
(,)Tj
0.83 0.64 0.02 0 k
(18)Tj
0 g
(,)Tj
0.83 0.64 0.02 0 k
(19)Tj
0 g
(],)Tj
5.6069 0 Td
(which)Tj
2.6476 0 Td
(contribute)Tj
4.3936 0 Td
(to)Tj
1.0262 0 Td
(its)Tj
1.1452 0 Td
(deleterious)Tj
-31.4927 -1.2982 Td
(effects.)Tj
2.948 0 Td
(Accumulation)Tj
5.93 0 Td
(of)Tj
1.0148 0 Td
(damaged)Tj
3.8494 0 Td
(protein)Tj
3.1521 0 Td
(in)Tj
1.0375 0 Td
(RPE)Tj
1.9729 0 Td
(cells)Tj
1.9162 0 Td
(is)Tj
0.8504 0 Td
(directly)Tj
3.2315 0 Td
(associated)Tj
4.2576 0 Td
(with)Tj
1.9956 0 Td
(AMD)Tj
2.5341 0 Td
(devel-)Tj
-34.6901 -1.2983 Td
(opment)Tj
3.3335 0 Td
([)Tj
0.83 0.64 0.02 0 k
(20)Tj
0 g
(].)Tj
2.0749 0 Td
(A2E)Tj
1.9502 0 Td
(photo-oxidation)Tj
6.7521 0 Td
(products)Tj
3.7531 0 Td
(also)Tj
1.7688 0 Td
(damage)Tj
3.3222 0 Td
(DNA)Tj
2.3754 0 Td
([)Tj
0.83 0.64 0.02 0 k
(21)Tj
0 g
(])Tj
1.8538 0 Td
(and)Tj
1.7292 0 Td
(activate)Tj
3.2541 0 Td
(the)Tj
1.4683 0 Td
(comple-)Tj
-33.6356 -1.3039 Td
(ment)Tj
2.3073 0 Td
(system)Tj
2.9424 0 Td
([)Tj
0.83 0.64 0.02 0 k
(22)Tj
0 g
(].)Tj
2.0749 0 Td
(The)Tj
1.7802 0 Td
(toxic)Tj
2.1826 0 Td
(activity)Tj
3.1181 0 Td
(of)Tj
1.0148 0 Td
(A2E)Tj
1.9502 0 Td
(photodegradation)Tj
7.3814 0 Td
(products)Tj
3.7531 0 Td
(was)Tj
1.7007 0 Td
(evidenced)Tj
4.235 0 Td
(by)Tj
-34.4407 -1.2983 Td
(incubating)Tj
4.507 0 Td
(RPE)Tj
1.9672 0 Td
(primary)Tj
3.4583 0 Td
(cell)Tj
1.559 0 Td
(cultures)Tj
3.3959 0 Td
(in)Tj
1.0375 0 Td
(the)Tj
1.4683 0 Td
(dark)Tj
2.0523 0 Td
(with)Tj
1.9956 0 Td
(a)Tj
0.6576 0 Td
(previously)Tj
4.3483 0 Td
(illuminated)Tj
4.8246 0 Td
(solution)Tj
3.4866 0 Td
(of)Tj
1.0148 0 Td
(A2E)Tj
-35.773 -1.2982 Td
([)Tj
0.83 0.64 0.02 0 k
(23)Tj
0 g
(].)Tj
1.1962 -1.2983 Td
(Given)Tj
2.6305 0 Td
(the)Tj
1.4683 0 Td
(direct)Tj
2.5342 0 Td
(involvement)Tj
5.21 0 Td
(of)Tj
1.0148 0 Td
(A2E)Tj
1.9503 0 Td
(in)Tj
1.0374 0 Td
(the)Tj
1.4684 0 Td
(pathology,)Tj
4.405 0 Td
(several)Tj
2.931 0 Td
(strategies)Tj
3.9231 0 Td
(have)Tj
2.0636 0 Td
(been)Tj
2.1203 0 Td
(consid-)Tj
-33.9531 -1.3039 Td
(ered)Tj
1.9672 0 Td
(for)Tj
1.3833 0 Td
(designing)Tj
4.0932 0 Td
(treatments,)Tj
4.7225 0 Td
(either)Tj
2.5341 0 Td
(by)Tj
1.1792 0 Td
(preventing)Tj
4.5411 0 Td
(the)Tj
1.4683 0 Td
(formation/accumulation)Tj
10.046 0 Td
(of)Tj
1.0148 0 Td
(this)Tj
1.6724 0 Td
(mole-)Tj
-34.6221 -1.2983 Td
(cule,)Tj
2.0636 0 Td
(or)Tj
1.0998 0 Td
(by)Tj
1.1792 0 Td
(counteracting/redu)Tj
7.7215 0 Td
(cing)Tj
1.9219 0 Td
(its)Tj
1.1452 0 Td
(deleterious)Tj
4.5978 0 Td
(effects)Tj
2.7269 0 Td
([)Tj
0.83 0.64 0.02 0 k
(24)Tj
0 g
(,)Tj
0.83 0.64 0.02 0 k
(25)Tj
0 g
(,)Tj
0.83 0.64 0.02 0 k
(26)Tj
0 g
(,)Tj
0.83 0.64 0.02 0 k
(27)Tj
0 g
(,)Tj
0.83 0.64 0.02 0 k
(28)Tj
0 g
(].)Tj
6.7804 0 Td
(Such)Tj
2.177 0 Td
(attempts)Tj
-31.4133 -1.2983 Td
(include)Tj
3.1804 0 Td
(\(list)Tj
1.7348 0 Td
(not)Tj
1.576 0 Td
(exhaustive\):)Tj
-6.4912 -1.8992 Td
(1.)Tj
1.2018 0 Td
(reducing)Tj
3.7701 0 Td
(A2E)Tj
1.9502 0 Td
(formation)Tj
4.2633 0 Td
(by)Tj
1.1792 0 Td
(retinylamine,)Tj
5.5502 0 Td
(a)Tj
0.652 0 Td
(visual)Tj
2.5114 0 Td
(pigment)Tj
3.5603 0 Td
(cycle)Tj
2.194 0 Td
(inhibitor)Tj
3.7758 0 Td
([)Tj
0.83 0.64 0.02 0 k
(29)Tj
0 g
(],)Tj
2.0806 0 Td
(by)Tj
1.1792 0 Td
(reducing)Tj
-32.6663 -1.3039 Td
(retinol)Tj
2.88 0 Td
(supply)Tj
2.846 0 Td
(to)Tj
1.0261 0 Td
(the)Tj
1.4684 0 Td
(retina)Tj
2.5625 0 Td
(by)Tj
1.1792 0 Td
(a)Tj
0.6576 0 Td
(RBP4)Tj
2.4548 0 Td
(inhibitor)Tj
3.7814 0 Td
([)Tj
0.83 0.64 0.02 0 k
(30)Tj
0 g
(])Tj
1.8482 0 Td
(or)Tj
1.0998 0 Td
(by)Tj
1.1792 0 Td
(feeding)Tj
3.1691 0 Td
(deuterium-enriched)Tj
8.2658 0 Td
(vita-)Tj
-34.4181 -1.2982 Td
(min)Tj
1.8539 0 Td
(A,)Tj
1.1282 0 Td
(which)Tj
2.6532 0 Td
(shows)Tj
2.6589 0 Td
(a)Tj
0.6519 0 Td
(reduced)Tj
3.4469 0 Td
(conversion)Tj
4.6318 0 Td
(into)Tj
1.8425 0 Td
(A2E)Tj
1.9502 0 Td
([)Tj
0.83 0.64 0.02 0 k
(31)Tj
0 g
(];)Tj
-22.0193 -1.8992 Td
(2.)Tj
1.2018 0 Td
(promoting)Tj
4.5184 0 Td
(A2E)Tj
1.9503 0 Td
(removal)Tj
3.4752 0 Td
(by)Tj
1.1849 0 Td
(intravitreal)Tj
4.6318 0 Td
(injection)Tj
3.7587 0 Td
(of)Tj
1.0148 0 Td
(cyclodextrins)Tj
5.5388 0 Td
([)Tj
0.83 0.64 0.02 0 k
(32)Tj
0 g
(,)Tj
0.83 0.64 0.02 0 k
(33)Tj
0 g
(])Tj
3.0274 0 Td
(or)Tj
1.0999 0 Td
(by)Tj
1.1792 0 Td
(promoting)Tj
-31.3794 -1.304 Td
(enzymatic)Tj
4.303 0 Td
(degradation)Tj
5.023 0 Td
(of)Tj
1.0148 0 Td
(A2E)Tj
1.9502 0 Td
([)Tj
0.83 0.64 0.02 0 k
(34)Tj
0 g
(,)Tj
0.83 0.64 0.02 0 k
(35)Tj
0 g
(];)Tj
-13.4928 -1.8992 Td
(3.)Tj
1.2018 0 Td
(reducing)Tj
3.7701 0 Td
(A2E)Tj
1.9502 0 Td
(oxidation)Tj
4.0422 0 Td
(by)Tj
1.1849 0 Td
(feeding)Tj
3.1634 0 Td
(natural)Tj
3.0784 0 Td
(antioxidants)Tj
5.176 0 Td
(\(carotenoids,)Tj
5.4539 0 Td
(flavonoids,)Tj
4.5864 0 Td
(resvera-)Tj
-32.4055 -1.2982 Td
(trol,)Tj
1.8652 0 Td
(etc.\))Tj
1.9332 0 Td
([)Tj
0.83 0.64 0.02 0 k
(36)Tj
0 g
(,)Tj
0.83 0.64 0.02 0 k
(37)Tj
0 g
(,)Tj
0.83 0.64 0.02 0 k
(38)Tj
0 g
(])Tj
4.201 0 Td
(or)Tj
1.0998 0 Td
(synthetic)Tj
3.8211 0 Td
(ones,)Tj
2.2903 0 Td
(e.g.)Tj
1.5591 0 Td
(PBN)Tj
2.0919 0 Td
(derivatives)Tj
4.5014 0 Td
([)Tj
0.83 0.64 0.02 0 k
(39)Tj
0 g
(];)Tj
-24.5648 -1.8992 Td
(4.)Tj
1.2018 0 Td
(counteracting)Tj
5.743 0 Td
(some)Tj
2.3244 0 Td
(A2E)Tj
1.9389 0 Td
(direct)Tj
2.5228 0 Td
(effects,)Tj
2.9423 0 Td
(such)Tj
2.0523 0 Td
(as)Tj
1.0035 0 Td
(treatments)Tj
4.49 0 Td
(for)Tj
1.3776 0 Td
(a)Tj
0.6407 0 Td
(re-acidification)Tj
6.3098 0 Td
(of)Tj
1.0092 0 Td
(lysosomes)Tj
-32.3545 -1.2983 Td
([)Tj
0.83 0.64 0.02 0 k
(40)Tj
0 g
(,)Tj
0.83 0.64 0.02 0 k
(41)Tj
0 g
(],)Tj
3.2485 0 Td
(or)Tj
1.0999 0 Td
(treatments)Tj
4.4957 0 Td
(aimed)Tj
2.6929 0 Td
(to)Tj
1.0261 0 Td
(restore)Tj
2.9764 0 Td
(efficient)Tj
3.4469 0 Td
(autophagic)Tj
4.6204 0 Td
(processes)Tj
3.9685 0 Td
([)Tj
0.83 0.64 0.02 0 k
(42)Tj
0 g
(];)Tj
-28.7771 -1.9049 Td
(5.)Tj
1.2018 0 Td
(counteracting)Tj
5.7543 0 Td
(long-term)Tj
4.252 0 Td
(consequences)Tj
5.6976 0 Td
(of)Tj
1.0148 0 Td
(A2E)Tj
1.9502 0 Td
(accumulation)Tj
5.6749 0 Td
(\(drusen)Tj
3.3222 0 Td
(formation\))Tj
4.5978 0 Td
(by)Tj
1.1848 0 Td
(using)Tj
-33.4486 -1.2982 Td
(inhibitors/antibodies)Tj
8.6116 0 Td
(to)Tj
1.0262 0 Td
(complement)Tj
5.244 0 Td
(alternative)Tj
4.422 0 Td
(pathway)Tj
3.5717 0 Td
([)Tj
0.83 0.64 0.02 0 k
(43)Tj
0 g
(].)Tj
-22.8811 -1.8992 Td
(Despite)Tj
3.2484 0 Td
(promising)Tj
4.3427 0 Td
(results,)Tj
3.0387 0 Td
(none)Tj
2.245 0 Td
(of)Tj
1.0148 0 Td
(these)Tj
2.2564 0 Td
(approaches)Tj
4.7338 0 Td
(has)Tj
1.5421 0 Td
(resulted)Tj
3.4015 0 Td
(up)Tj
1.2643 0 Td
(to)Tj
1.0261 0 Td
(now)Tj
1.9616 0 Td
(in)Tj
1.0318 0 Td
(a)Tj
0.6576 0 Td
(recognized)Tj
-32.961 -1.2983 Td
(efficient)Tj
3.4469 0 Td
(treatment)Tj
4.1328 0 Td
(of)Tj
1.0148 0 Td
(dry)Tj
1.5761 0 Td
(AMD.)Tj
2.7609 0 Td
(Current)Tj
3.4243 0 Td
(treatments)Tj
4.4957 0 Td
(have)Tj
2.0579 0 Td
(a)Tj
0.652 0 Td
(limited)Tj
3.0727 0 Td
(efficacy)Tj
3.2202 0 Td
(and)Tj
1.7291 0 Td
(and)Tj
1.7348 0 Td
(rely)Tj
1.7121 0 Td
(on)Tj
-35.0303 -1.3039 Td
(nutritional)Tj
4.524 0 Td
(formulae)Tj
3.8268 0 Td
(containing)Tj
4.5184 0 Td
(zinc,)Tj
2.0919 0 Td
(various)Tj
3.1351 0 Td
(antioxidants)Tj
5.1647 0 Td
(\(vitamins)Tj
4.0025 0 Td
(C)Tj
0.8731 0 Td
(and)Tj
1.7234 0 Td
(E\))Tj
1.1169 0 Td
(and)Tj
1.7234 0 Td
(carotenoids,)Tj
-32.7002 -1.2983 Td
(whose)Tj
2.7212 0 Td
(components)Tj
5.176 0 Td
(have)Tj
2.058 0 Td
(been)Tj
2.1259 0 Td
(tested)Tj
2.5512 0 Td
(either)Tj
2.5285 0 Td
(individually)Tj
4.9889 0 Td
(or)Tj
1.0999 0 Td
(as)Tj
1.0148 0 Td
(various)Tj
3.1407 0 Td
(mixtures)Tj
3.7587 0 Td
(over)Tj
1.9729 0 Td
(several)Tj
-33.1367 -1.2982 Td
(years)Tj
2.262 0 Td
(\(AREDS)Tj
3.651 0 Td
(1)Tj
0.6916 0 Td
(and)Tj
1.7292 0 Td
(2)Tj
0.6973 0 Td
(studies\).)Tj
3.5546 0 Td
(These)Tj
2.5625 0 Td
(studies)Tj
2.9877 0 Td
(have)Tj
2.0579 0 Td
(indeed)Tj
2.9424 0 Td
(established)Tj
4.5977 0 Td
(the)Tj
1.4684 0 Td
(protective)Tj
4.2009 0 Td
(role)Tj
1.7688 0 Td
(of)Tj
-35.172 -1.304 Td
(zinc)Tj
1.8708 0 Td
(and,)Tj
1.9559 0 Td
(for)Tj
1.3833 0 Td
(a)Tj
0.6576 0 Td
(part)Tj
1.8425 0 Td
(of)Tj
1.0148 0 Td
(the)Tj
1.4684 0 Td
(population)Tj
4.5864 0 Td
(tested,)Tj
2.7779 0 Td
(of)Tj
1.0148 0 Td
(carotenoids)Tj
4.8926 0 Td
([)Tj
0.83 0.64 0.02 0 k
(44)Tj
0 g
(,)Tj
0.83 0.64 0.02 0 k
(45)Tj
0 g
(].)Tj
-22.2688 -1.2982 Td
(The)Tj
1.7858 0 Td
(rationale)Tj
3.7474 0 Td
(for)Tj
1.3889 0 Td
(using)Tj
2.3868 0 Td
(specific)Tj
3.1918 0 Td
(carotenoids)Tj
4.8869 0 Td
(\(lutein,)Tj
3.1011 0 Td
(zeaxanthin)Tj
4.5807 0 Td
(and)Tj
1.7291 0 Td
(meso-zeaxanthin\))Tj
7.3814 0 Td
(relies)Tj
-35.3761 -1.2983 Td
(on)Tj
1.2755 0 Td
(the)Tj
1.4684 0 Td
(fact)Tj
1.6611 0 Td
(that)Tj
1.7801 0 Td
(they)Tj
1.9276 0 Td
(are)Tj
1.4456 0 Td
(naturally)Tj
3.7814 0 Td
(present)Tj
3.1635 0 Td
(in)Tj
1.0374 0 Td
(the)Tj
1.4684 0 Td
(macula.)Tj
3.3278 0 Td
(As)Tj
1.2699 0 Td
(with)Tj
1.9956 0 Td
(other)Tj
2.3471 0 Td
(antioxidants,)Tj
5.4028 0 Td
(their)Tj
2.1089 0 Td
(bio-)Tj
-35.4611 -1.2982 Td
(logical)Tj
2.8062 0 Td
(activity)Tj
3.1181 0 Td
(is)Tj
0.8504 0 Td
(not)Tj
1.5704 0 Td
(limited)Tj
3.0727 0 Td
(to)Tj
1.0262 0 Td
(an)Tj
1.2018 0 Td
(antioxidant)Tj
4.8132 0 Td
(effect)Tj
2.3641 0 Td
([)Tj
0.83 0.64 0.02 0 k
(46)Tj
0 g
(,)Tj
0.83 0.64 0.02 0 k
(47)Tj
0 g
(].)Tj
3.2542 0 Td
(They)Tj
2.2393 0 Td
(are)Tj
1.4457 0 Td
(expected)Tj
3.7247 0 Td
(to)Tj
1.0261 0 Td
(act)Tj
1.3777 0 Td
(there)Tj
2.262 0 Td
(as)Tj
-36.1528 -1.304 Td
(filters)Tj
2.4717 0 Td
(for)Tj
1.389 0 Td
(blue)Tj
1.9219 0 Td
(light)Tj
2.0239 0 Td
([)Tj
0.83 0.64 0.02 0 k
(48)Tj
0 g
(],)Tj
2.0806 0 Td
(as)Tj
1.0148 0 Td
(antioxidants)Tj
5.1761 0 Td
([)Tj
0.83 0.64 0.02 0 k
(49)Tj
0 g
(],)Tj
2.0749 0 Td
(to)Tj
1.0261 0 Td
(display)Tj
3.0274 0 Td
(anti-inflammatory)Tj
7.6082 0 Td
(properties)Tj
4.2803 0 Td
([)Tj
0.83 0.64 0.02 0 k
(50)Tj
0 g
(])Tj
1.8481 0 Td
(and)Tj
-35.943 -1.2982 Td
(to)Tj
1.0261 0 Td
(attenuate)Tj
3.9061 0 Td
(A2E)Tj
1.9446 0 Td
(formation)Tj
4.2632 0 Td
([)Tj
0.83 0.64 0.02 0 k
(36)Tj
0 g
(].)Tj
-9.9438 -1.2983 Td
(We)Tj
1.61 0 Td
(previously)Tj
4.354 0 Td
(observed)Tj
3.7928 0 Td
(the)Tj
1.4683 0 Td
(photo-protective)Tj
6.9165 0 Td
(activity)Tj
3.1181 0 Td
(of)Tj
1.0148 0 Td
(two)Tj
1.7064 0 Td
(diapocarotenoids,)Tj
7.37 0 Td
(bixin)Tj
2.2734 0 Td
(and)Tj
-34.8205 -1.3039 Td
(norbixin)Tj
3.6906 0 Td
(\()Tj
0.83 0.64 0.02 0 k
(Fig)Tj
1.8142 0 Td
(1)Tj
0 g
(\),)Tj
1.2529 0 Td
(for)Tj
1.3776 0 Td
(skin)Tj
1.8822 0 Td
(cells)Tj
1.9162 0 Td
(against)Tj
3.0161 0 Td
(UVB)Tj
2.2223 0 Td
([)Tj
0.83 0.64 0.02 0 k
(51)Tj
0 g
(])Tj
1.8482 0 Td
(and)Tj
1.7178 0 Td
(these)Tj
2.245 0 Td
(data)Tj
1.9106 0 Td
(prompted)Tj
4.1895 0 Td
(us)Tj
1.1055 0 Td
(to)Tj
1.0148 0 Td
(engage)Tj
2.9707 0 Td
(in)Tj
1.0262 0 Td
(a)Tj
0.6463 0 Td
(pro-)Tj
-35.8467 -1.2983 Td
(gramme)Tj
3.5546 0 Td
(for)Tj
1.3833 0 Td
(assessing)Tj
3.804 0 Td
(the)Tj
1.4684 0 Td
(potential)Tj
3.7587 0 Td
(of)Tj
1.0148 0 Td
(these)Tj
2.2564 0 Td
(molecules)Tj
4.1952 0 Td
(for)Tj
1.389 0 Td
(the)Tj
1.4683 0 Td
(treatment)Tj
4.1386 0 Td
(of)Tj
1.0148 0 Td
(dry)Tj
1.5703 0 Td
(AMD.)Tj
2.761 0 Td
(For)Tj
1.6271 0 Td
(that)Tj
ET
Q
q
1 j
1 J
0 w
576 737.1 m
36 737.1 l
36 737.6 l
576 737.6 l
f*
36 741.2598 107.1496 23.6976 re
W* n
q
107.0929 0 0 23.6409 36 741.3165 cm
q
/I0 Do
Q
Q
Q
q
0 0 612 792 re
W* n
1 j
1 J
0 w
7.9999 0 0 7.9999 402.633 745.7952 cm
BT
/F0 1 Tf
1 TL
-0.005 Tc
0 0 Td
(Norbixin)Tj
3.8126 0 Td
(Protecti)Tj
3.3307 0 Td
(on)Tj
1.311 0 Td
(in)Tj
0.978 0 Td
(Retinal)Tj
3.274 0 Td
(Phototo)Tj
3.3875 0 Td
(xicity)Tj
2.4024 0 Td
(Models)Tj
ET
Q
q
1 j
1 J
0 w
36 48.0002 m
576 48.0002 l
576 47.5002 l
36 47.5002 l
f*
7.9999 0 0 7.9999 36 36 cm
BT
/F0 1 Tf
1 TL
-0.005 Tc
0 0 Td
(PLOS)Tj
2.8559 0 Td
(ONE)Tj
2.3669 0 Td
(|)Tj
0.4748 0 Td
(DOI:10.137)Tj
5.0387 0 Td
(1/journal.po)Tj
5.1236 0 Td
(ne.0167)Tj
3.5434 0 Td
(793)Tj
2.6362 0 Td
(December)Tj
4.7622 0 Td
(16,)Tj
1.5874 0 Td
(2016)Tj
36.7515 0 Td
(2)Tj
0.7654 0 Td
(/)Tj
0.496 0 Td
(25)Tj
/F10 1 Tf
-0.025 Tc
-66.402 84.0904 Td
(participate)Tj
3.8338 0 Td
(d)Tj
0.6945 0 Td
(to)Tj
0.9496 0 Td
(the)Tj
1.3678 0 Td
(design)Tj
2.6787 0 Td
(and)Tj
1.5874 0 Td
(realization)Tj
3.9332 0 Td
(of)Tj
0.9496 0 Td
(the)Tj
-15.9946 -1.3748 Td
(experimen)Tj
3.8834 0 Td
(ts.)Tj
1.1268 0 Td
(They)Tj
2.0056 0 Td
(declare,)Tj
3.1039 0 Td
(however,)Tj
3.6071 0 Td
(that)Tj
1.6229 0 Td
(their)Tj
-15.3497 -1.3749 Td
(potential)Tj
3.3803 0 Td
(commercial)Tj
4.578 0 Td
(interests)Tj
3.3945 0 Td
(had)Tj
1.5874 0 Td
(no)Tj
1.1622 0 Td
(impact)Tj
2.7426 0 Td
(on)Tj
-16.845 -1.3748 Td
(the)Tj
1.3677 0 Td
(scientific)Tj
3.4724 0 Td
(conduct)Tj
3.2103 0 Td
(of)Tj
0.9496 0 Td
(the)Tj
1.3677 0 Td
(study)Tj
2.2678 0 Td
(or)Tj
0.9992 0 Td
(the)Tj
1.3748 0 Td
(analys)Tj
2.3457 0 Td
(is/)Tj
-17.3552 -1.3748 Td
(interpretati)Tj
3.9756 0 Td
(on)Tj
1.1693 0 Td
(of)Tj
0.9496 0 Td
(data.)Tj
2.0126 0 Td
(The)Tj
1.5874 0 Td
(grant)Tj
2.1544 0 Td
(providers)Tj
3.7134 0 Td
(\(FEDER)Tj
-15.5623 -1.3748 Td
(and)Tj
1.5874 0 Td
(City)Tj
1.6157 0 Td
(of)Tj
0.9496 0 Td
(Paris\))Tj
2.3953 0 Td
(had)Tj
1.5874 0 Td
(no)Tj
1.1693 0 Td
(role)Tj
1.6158 0 Td
(in)Tj
0.8858 0 Td
(study)Tj
2.2607 0 Td
(design,)Tj
2.9055 0 Td
(data)Tj
-16.9725 -1.3748 Td
(collection)Tj
3.7417 0 Td
(and)Tj
1.5874 0 Td
(analysis)Tj
2.9623 0 Td
(,)Tj
0.4464 0 Td
(decision)Tj
3.2882 0 Td
(to)Tj
0.9496 0 Td
(publish,)Tj
3.1465 0 Td
(or)Tj
-16.1221 -1.3748 Td
(preparation)Tj
4.4433 0 Td
(of)Tj
0.9496 0 Td
(the)Tj
1.3677 0 Td
(manuscript.)Tj
4.6347 0 Td
(The)Tj
1.5945 0 Td
(City)Tj
1.6087 0 Td
(of)Tj
0.9496 0 Td
(Paris)Tj
-15.5481 -1.3748 Td
(grant)Tj
2.1543 0 Td
(supporte)Tj
3.2953 0 Td
(d)Tj
0.6945 0 Td
(in)Tj
0.8858 0 Td
(particular)Tj
3.6851 0 Td
(the)Tj
1.3748 0 Td
(salaries)Tj
3.0189 0 Td
(of)Tj
0.9496 0 Td
(the)Tj
-16.0583 -1.3748 Td
(three)Tj
2.0976 0 Td
(engineers)Tj
3.8268 0 Td
(\(EM,)Tj
1.9772 0 Td
(EB,)Tj
1.4457 0 Td
(LL\).)Tj
1.7008 0 Td
(PPE)Tj
1.7433 0 Td
(and)Tj
1.5874 0 Td
(LF)Tj
1.1126 0 Td
(are)Tj
-15.4914 -1.3749 Td
(employees)Tj
4.2236 0 Td
(of)Tj
0.9496 0 Td
(Iris)Tj
1.3961 0 Td
(Pharma,)Tj
3.3449 0 Td
(while)Tj
2.1402 0 Td
(CB,)Tj
1.4953 0 Td
(LG,)Tj
1.5023 0 Td
(SV)Tj
1.2756 0 Td
(and)Tj
1.5875 0 Td
(RL)Tj
-17.9151 -1.3748 Td
(are)Tj
1.3677 0 Td
(employees)Tj
4.2236 0 Td
(of)Tj
0.9496 0 Td
(Biophytis.)Tj
/F9 1 Tf
-6.5409 -2.126 Td
(Competing)Tj
4.3795 0 Td
(Interests)Tj
3.3307 0 Td
(:)Tj
/F10 1 Tf
0.4819 0 Td
(A)Tj
0.7441 0 Td
(patent)Tj
2.5158 0 Td
(Composition)Tj
5.2938 0 Td
(for)Tj
-16.7458 -1.3748 Td
(the)Tj
1.3677 0 Td
(protection)Tj
3.9685 0 Td
(of)Tj
0.9496 0 Td
(retinal)Tj
2.4874 0 Td
(pigment)Tj
3.2599 0 Td
(epithelium)Tj
-12.0331 -1.3748 Td
(covering)Tj
3.4016 0 Td
(the)Tj
1.3748 0 Td
(topic)Tj
2.0338 0 Td
(of)Tj
0.9497 0 Td
(this)Tj
1.5661 0 Td
(manuscr)Tj
3.267 0 Td
(ipt)Tj
1.148 0 Td
(has)Tj
1.5307 0 Td
(been)Tj
2.0126 0 Td
(filed)Tj
-17.2843 -1.3748 Td
(on)Tj
1.1693 0 Td
(April)Tj
1.9063 0 Td
(30,)Tj
1.396 0 Td
(2015)Tj
2.1119 0 Td
(\(FR)Tj
1.5378 0 Td
(15)Tj
1.1622 0 Td
(53957\))Tj
2.8984 0 Td
(and)Tj
1.5874 0 Td
(is)Tj
0.8363 0 Td
(owned)Tj
2.7 0 Td
(by)Tj
-17.3056 -1.3748 Td
(Stanislas)Tj
3.5433 0 Td
(Veillet,)Tj
2.6504 0 Td
(Rene)Tj
0 Tc
1.5449 0.0283 Td
()Tj
-0.025 Tc
0.5811 -0.0283 Td
(Lafont,)Tj
2.7921 0 Td
(Jose)Tj
0 Tc
1.3819 0.0283 Td
()Tj
-0.025 Tc
0.3544 -0.0283 Td
(-Alain)Tj
2.3386 0 Td
(Sahel,)Tj
-15.1867 -1.3748 Td
(Vale)Tj
0 Tc
1.2047 0.0283 Td
()Tj
-0.025 Tc
0.3543 -0.0283 Td
(rie)Tj
1.141 0 Td
(Fontaine)Tj
3.3591 0 Td
(and)Tj
1.5874 0 Td
(Pierre-Paul)Tj
4.3157 0 Td
(Elena.)Tj
2.4237 0 Td
(PP)Tj
1.2756 0 Td
(Elena)Tj
2.1969 0 Td
(is)Tj
-17.8584 -1.3749 Td
(chairman)Tj
3.685 0 Td
(of)Tj
0.9496 0 Td
(the)Tj
1.3678 0 Td
(Board)Tj
2.4236 0 Td
(of)Tj
0.9496 0 Td
(Iris)Tj
1.3961 0 Td
(Pharma)Tj
3.1252 0 Td
(and)Tj
1.5874 0 Td
(is)Tj
-15.4843 -1.3748 Td
(shareholder)Tj
4.6063 0 Td
(of)Tj
0.9496 0 Td
(the)Tj
1.3677 0 Td
(Society.)Tj
3.1607 0 Td
(R)Tj
0.8079 0 Td
(Lafont)Tj
2.5724 0 Td
(is)Tj
0.8292 0 Td
(founder,)Tj
-14.2938 -1.3748 Td
(CSO)Tj
1.8567 0 Td
(and)Tj
1.5874 0 Td
(shareholder)Tj
4.6063 0 Td
(of)Tj
0.9496 0 Td
(Biophytis.)Tj
3.8764 0 Td
(S.)Tj
0.9709 0 Td
(Veillet)Tj
2.4236 0 Td
(is)Tj
-16.2709 -1.3748 Td
(founder,)Tj
3.3236 0 Td
(CEO)Tj
1.8071 0 Td
(and)Tj
1.5874 0 Td
(shareholder)Tj
4.6063 0 Td
(of)Tj
0.9497 0 Td
(Biophytis.)Tj
3.8693 0 Td
(This)Tj
-16.1434 -1.3748 Td
(does)Tj
2.0126 0 Td
(not)Tj
1.4173 0 Td
(alter)Tj
1.8213 0 Td
(our)Tj
1.474 0 Td
(adherence)Tj
4.0536 0 Td
(to)Tj
0.9496 0 Td
(PLOS)Tj
2.3315 0 Td
(ONE)Tj
1.8709 0 Td
(policies)Tj
-15.9308 -1.3748 Td
(on)Tj
1.1693 0 Td
(sharing)Tj
2.9834 0 Td
(data)Tj
1.7859 0 Td
(and)Tj
1.5945 0 Td
(material)Tj
2.9622 0 Td
(s.)Tj
0.8646 0 Td
(We)Tj
1.4527 0 Td
(have)Tj
1.956 0 Td
(no)Tj
-14.7686 -1.3819 Td
(restrictio)Tj
3.2456 0 Td
(n)Tj
0.6945 0 Td
(to)Tj
0.9497 0 Td
(share)Tj
2.2677 0 Td
(these)Tj
2.211 0 Td
(data.)Tj
/F9 1 Tf
-9.3685 -2.1189 Td
(Abbreviati)Tj
3.9118 0 Td
(ons:)Tj
/F10 1 Tf
1.8425 0 Td
(A2E,)Tj
/F11 1 Tf
1.9205 0 Td
(N)Tj
/F10 1 Tf
(-retinylide)Tj
4.2449 0 Td
(ne-)Tj
/F11 1 Tf
(N)Tj
/F10 1 Tf
(-)Tj
-11.9197 -1.3749 Td
(retinyletha)Tj
3.8338 0 Td
(nolamine;)Tj
3.8481 0 Td
(AMD,)Tj
2.3103 0 Td
(age-related)Tj
4.337 0 Td
(macular)Tj
-14.3292 -1.3748 Td
(degeneration;)Tj
5.2512 0 Td
(AUC,)Tj
2.0835 0 Td
(area)Tj
1.7929 0 Td
(under)Tj
2.3669 0 Td
(curve;)Tj
2.4874 0 Td
(BLD,)Tj
2.0339 0 Td
(blue-)Tj
-16.0158 -1.3748 Td
(light-induce)Tj
4.3512 0 Td
(d)Tj
0.6945 0 Td
(retinal)Tj
2.4874 0 Td
(damage;)Tj
3.4087 0 Td
(DMSO,)Tj
-10.9418 -1.3819 Td
(dimethylsulf)Tj
4.5283 0 Td
(oxide;)Tj
2.4237 0 Td
(ERG,)Tj
2.0976 0 Td
(electrore)Tj
3.2174 0 Td
(tinogram;)Tj
3.7984 0 Td
(HPLC,)Tj
-16.0654 -1.3748 Td
(high-perfo)Tj
3.848 0 Td
(rmance)Tj
3.0189 0 Td
(liquid)Tj
2.2252 0 Td
(chromatogr)Tj
4.3583 0 Td
(aphy;)Tj
2.2324 0 Td
(HPLC-)Tj
-15.6828 -1.3748 Td
(MS/MS,)Tj
3.2598 0 Td
(HPLC)Tj
2.3315 0 Td
(coupled)Tj
3.1465 0 Td
(with)Tj
1.7859 0 Td
(tandem)Tj
3.0189 0 Td
(mass)Tj
-13.5426 -1.3748 Td
(spectrome)Tj
3.9472 0 Td
(try;)Tj
1.4315 0 Td
(MRM,)Tj
2.5371 0 Td
(Multiple)Tj
3.1748 0 Td
(Reaction)Tj
3.4725 0 Td
(Monitori)Tj
3.1181 0 Td
(ng;)Tj
-17.6812 -1.3748 Td
(ONL,)Tj
2.0905 0 Td
(outer)Tj
2.1544 0 Td
(nuclear)Tj
2.9338 0 Td
(layer;)Tj
2.204 0 Td
(OS,)Tj
1.5591 0 Td
(outer)Tj
2.1472 0 Td
(segments;)Tj
4.089 0 Td
(INL,)Tj
-17.178 -1.3749 Td
(inner)Tj
2.0905 0 Td
(nuclear)Tj
2.9268 0 Td
(layer;)Tj
2.2111 0 Td
(GCL,)Tj
2.0338 0 Td
(ganglion)Tj
3.3945 0 Td
(cell)Tj
1.4457 0 Td
(layer;)Tj
2.2111 0 Td
(PBN,)Tj
-16.3135 -1.3748 Td
(Phenyl-N)Tj
/F11 1 Tf
(-te)Tj
4.3866 0 Td
(rt)Tj
/F10 1 Tf
(-Butylnitrone)Tj
5.3363 0 Td
(;)Tj
0.4464 0 Td
(PBS,)Tj
2.0197 0 Td
(phosphate)Tj
4.1032 0 Td
(buffer)Tj
-16.2922 -1.3748 Td
(saline;)Tj
2.5653 0 Td
(PPAR,)Tj
2.6079 0 Td
(Peroxisome)Tj
4.6347 0 Td
(proliferator-)Tj
4.3866 0 Td
(activated)Tj
-14.1945 -1.3748 Td
(receptor;)Tj
3.522 0 Td
(RPE,)Tj
2.0339 0 Td
(retinal)Tj
2.4874 0 Td
(pigment)Tj
ET
endstream
endobj
70 0 obj
<>stream
endstream
endobj
71 0 obj
<>stream
endstream
endobj
72 0 obj
<>stream
endstream
endobj
73 0 obj
<>stream
endstream
endobj
74 0 obj
<>stream
endstream
endobj
75 0 obj
<>stream
endstream
endobj
76 0 obj
<>stream
endstream
endobj
77 0 obj
<>stream
endstream
endobj
78 0 obj
<>stream
endstream
endobj
79 0 obj
<>stream
endstream
endobj
80 0 obj
<>stream
endstream
endobj
81 0 obj
<>stream
endstream
endobj
82 0 obj
<>stream
endstream
endobj
83 0 obj
<>stream
endstream
endobj
84 0 obj
<>stream
endstream
endobj
85 0 obj
<>stream
endstream
endobj
86 0 obj
<>stream
endstream
endobj
87 0 obj
<>stream
endstream
endobj
88 0 obj
<>stream
endstream
endobj
89 0 obj
<>stream
endstream
endobj
90 0 obj
<>stream
endstream
endobj
91 0 obj
<>stream
endstream
endobj
92 0 obj
<>stream
endstream
endobj
93 0 obj
<>stream
endstream
endobj
94 0 obj
<>stream
endstream
endobj
95 0 obj
<>stream
endstream
endobj
96 0 obj
<>stream
endstream
endobj
97 0 obj
<>stream
endstream
endobj
98 0 obj
<>stream
endstream
endobj
99 0 obj
<>stream
endstream
endobj
100 0 obj
<>stream
endstream
endobj
101 0 obj
<>stream
endstream
endobj
102 0 obj
<>stream
endstream
endobj
103 0 obj
<>stream
endstream
endobj
104 0 obj
<>stream
endstream
endobj
105 0 obj
<>stream
endstream
endobj
106 0 obj
<>stream
endstream
endobj
107 0 obj
<>stream
endstream
endobj
108 0 obj
<>stream
endstream
endobj
109 0 obj
<>stream
endstream
endobj
110 0 obj
<>stream
endstream
endobj
111 0 obj
<>stream
endstream
endobj
112 0 obj
<>stream
endstream
endobj
113 0 obj
<>stream
endstream
endobj
114 0 obj
<>stream
endstream
endobj
115 0 obj
<>stream
endstream
endobj
116 0 obj
<>stream
endstream
endobj
117 0 obj
<>stream
endstream
endobj
118 0 obj
<>stream
endstream
endobj
119 0 obj
<>stream
BT
11.3032 31.7128 Td
(epithelium.)Tj
ET
Q
endstream
endobj
120 0 obj
<>/XObject<>>>/CropBox[0 0 612 792]/MediaBox[0 0 612 792]/Parent 12 0 R/Annots 125 0 R/Contents 126 0 R/TrimBox[0 0 612 792]>>
endobj
124 0 obj
<>stream
JFIF C
$, !$4.763.22:ASF:=N>22HbINVX]^]8EfmeZlS[]Y C**Y;2;YYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYY cu"
} !1AQa"q2#BR$3br
%&'()*456789:CDEFGHIJSTUVWXYZcdefghijstuvwxyz
w !1AQaq"2B #3Rbr
$4%&'()*56789:CDEFGHIJSTUVWXYZcdefghijstuvwxyz ? (
(
(
(
(
(
(
(
(
(
(
(
(
(
(
(
(
(
(
(
(
(
(
(
(
(
(
(
(Mr-Nki0UO8ڠ>jysM^Ki%cZG\IZΑBk;ZTyaa7LӶmOSxV@]erajr>*b4m!3N?Wh.0}( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( F$)#(' n.ߢ/j7YS:Wo;o@g`G y߆