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ORIGINAL ARTICLE

Comparison of transepithelial cornealcollagen crosslinking with epithelium-offcrosslinking in progressive keratoconus�

Comparaison entre le cross-linking du collagène cornéentransépithélial et le cross-linking conventionnel dans lekératocône évolutif

I. Kocaka, A. Aydina,b,∗, F. Kayaa, H. Kocc

a Service d’ophtalmologie, hôpital de Nisa, Istanbul, Turkeyb Clinique universitaire d’ophtalmologie, faculté de médecine, université d’Istanbul Medipol,Istanbul, Turkeyc Service d’ophtalmologie, hôpital de Kent, Kutahya, Turkey

Received 31 July 2013; accepted 22 November 2013

KEYWORDSKeratoconus;Corneal collagencrosslinking;Transepithelial

SummaryPurpose. — To evaluate the safety and efficacy of transepithelial corneal collagen crosslinking(TE-CXL) as compared to epithelium-off crosslinking (epi-off CXL) in progressive keratoconus.Methods. — Records of keratoconus patients treated with TE-CXL or epi-off CXL were reviewedretrospectively. Patients were included if they had at least 12 months follow-up. Pre- and post-operative measurements of visual acuity, refractive errors, keratometry, corneal topographyand pachymetry were assessed and compared.Results. — There was no statistically significant difference between two groups at baseline interms of demographic, refractive and corneal parameters. Mean maximum cone apex curvature(apical K) increased from 51.62 ± 5. Eighty-four diopters (D) to 53.70 ± 5.49 D in the TE-CXL

group (n = 17), and decreased from 52.02 ± 4.07 D to 51.22 ± 3.51 in the epi-off CXL group (n = 19) at the end of the follow-up period. The difference between two groups was statistically

Please cite this article in press as: Kocak I, et al. Comparison of transepithelial corneal colla-gen crosslinking with epithelium-off crosslinking in progressive keratoconus. J Fr Ophtalmol (2014),http://dx.doi.org/10.1016/j.jfo.2013.11.012

significant (P = 0.0002). An increase of ≥ 1D in apical K was observed in two of 19 eyes (11%) in theepi-off CXL group, and 11 of 17 eyes (65%) in TE-CXL group at the last follow-up visit, comparedto baseline (P < 0.0001). Fourteen patients in the epi-off CXL group exhibited corneal edema

� Presented at the 47th Annual Congress of the Turkish Society of Ophthalmology, November 2013, Antalya, Turkey.∗ Corresponding author. Özel Nisa Hastanesi, Göz Hastalıkları Servisi, Fatih Caddesi, Yenibosna, Turkey.

E-mail addresses: aliaydin67@hotmail.com, aaydin@medipol.edu.tr (A. Aydin).

http://dx.doi.org/10.1016/j.jfo.2013.11.0120181-5512/© 2014 Elsevier Masson SAS. All rights reserved.

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that resolved without haze with topical corticosteroid treatment by 4 months. No postoperativecorneal edema was observed in TE-CXL group.Conclusions. — Although it is safe and well tolerated, TE-CXL does not effectively halt theprogression of keratoconus. Epi-off CXL appears to be effective in stopping progression andeven improves corneal parameters.© 2014 Elsevier Masson SAS. All rights reserved.

MOTS CLÉSKératocône ;Cross-linking ducollagène cornéen ;Transépithélial

RésuméObjectif. — Évaluer l’efficacité et l’innocuité du cross-linking du collagène cornéen transép-ithélial (TE-CXL) par rapport au cross-linking conventionnel (épi-off CXL) dans le traitement dukératocône évolutif.Patients et méthodes. — Les patients atteints de kératocône traités par TE-CXL ou épi-off CXLont été revus rétrospectivement. Les patients ont été inclus s’ils avaient au moins 12 mois desuivi. Les mesures pré- et postopératoires de l’acuité visuelle, des erreurs de réfraction, de lakératométrie, de la topographie cornéenne et de la pachymétrie ont été évaluées et comparées.Résultats. — Il n’y avait pas de différence statistiquement significative entre les paramètrespréopératoires des deux groupes concernant les donnés démographiques, les données réfrac-tives et topographiques cornéennes. La valeur moyenne de la courbure maximale du sommet ducône (apical K) a augmenté de 51,62 ± 5,84 dioptres (D) à 53,70 ± 5,49 D dans le groupe de TE-CXL (n = 17) et diminué de 52,02 ± 4,07 D à 51,22 ± 3,51 D dans le groupe d’épi-off CXL (n = 19)à la fin de la période de suivi. La différence entre les deux groupes était statistiquement signi-ficative (p = 0,0002). Une augmentation supérieure à 1 dioptrie d’apical K a été observée dans11 % (2/19) du groupe d’épi-off CXL et 65 % (11/17) du groupe de TE-CXL, lors de la dernièrevisite de suivi, par rapport aux mesures préopératoires (p < 0,0001). Quatorze patients dans legroupe d’épi-off CXL ont présenté un œdème cornéen toujours résolutif avant 4 mois avec unecorticothérapie topique. Il n’a pas été observé d’œdème cornéen postopératoire dans le groupede TE-CXL.Conclusions. — Malgré une sécurité et une tolérance démontrées, le TE-CXL ne semble pasarrêter efficacement la progression du kératocône. Le cross-linking conventionnel est plus effi-cace dans la stabilisation du kératocône en améliorant même ses paramètres topographiquescornéens.© 2014 Elsevier Masson SAS. Tous droits réservés.

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ntroduction

eratoconus is a non-inflammatory, progressive, bilateralisorder of the eye in which the cornea assumes a conicalhape secondary to biomechanical changes [1]. This ectaticorneal disorder has an incidence of approximately 1/2000.ts onset is usually at puberty and progresses until the fourthecade of life, after which it typically stabilizes [2]. Progres-ion of keratoconus was a challenging issue to handle, untilhe definition of corneal collagen crosslinking (CXL) whichs a novel surgical procedure increasing the rigidity of theorneal tissue. It has been reported that CXL is effectivelytopping the progression of corneal ectatic diseases includ-ng keratoconus by creating extra crosslinks in the cornealtroma [3—6].

CXL promotes the photopolymerization of collagen fibersnduced by ultraviolet A (UVA) light in the presence ofiboflavin as a photosensitizing substance. The effect of CXLs based on the augmentation of the number of intrafibril-

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ar and interfibrillar covalent bonds. Since riboflavin cannotasily penetrate intact corneal epithelium, removal ofpithelium is necessary for the classic CXL procedure (epi-ff CXL). However, the removal of epithelium can cause

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evere postoperative pain and temporary visual blurring. Tovoid these problems, some authors designed transepithe-ial CXL (TE-CXL) based on the use of a special riboflavinolution which can penetrate the intact epithelium [7]. Inhis study we aimed to evaluate and compare the efficacynd safety of epi-off CXL and TE-CXL procedures.

ethods

atients

ubjects enrolled in the study were consecutive keratoconusatients who underwent TE- or epi-off CXL at the Nisa Hos-ital, Istanbul, Turkey, from January 2009 to July 2012. Thetudy was conducted in accordance with the Declaration ofelsinki and approved by the institutional ethics committee.

nformed consent was signed by all patients. We retrospec-ively reviewed the data of patients with a diagnosis of

al. Comparison of transepithelial corneal colla-progressive keratoconus. J Fr Ophtalmol (2014),

eratoconus who underwent TE- or epi-off CXL. Inclusionriteria were presence of keratoconus, clear cornea at slit-amp examination, central corneal thickness greater than00 �m, evidence of progression documented by an increase

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ARTICLEJFO-931; No. of Pages 6

Transepithelial and epithelium-off crosslinking in keratoconu

of at least 1.00 diopter (D) in the maximum cone apex cur-vature (Apical K) or an increase of at least 1.00 D in centralcorneal astigmatism over the previous 6 months. Exclusioncriteria included apical scarring, active keratitis, any otheranterior or posterior segment disorder, and concomitantautoimmune disease. Contact lens wear was discontinuedone month before the initial examination in all patients.

All patients had a full ophthalmologic examination,including the objective refraction, uncorrected and bestspectacle corrected Snellen visual acuity (UCVA andBSCVA), slit lamp examination, posterior segment exam-ination, intraocular pressure measurement, keratometry,pachymetry and corneal topography (Orbscan II, Bausch &Lomb, Rochester, NY, USA), at the preoperative and postop-erative visits. Postoperative follow-up visits were scheduledat the 1st, 4th,7th, 30th day and the 3rd, 6th, 12thmonth after surgery, and then yearly. Patients with at least12 months follow-up were included in the study.

Surgical procedure

Epi-off CXL was performed under topical anesthesia.Proparacaine 0,5% was administered every 5 minutes begin-ning 20 minutes before surgery. Miosis was induced withpilocarpine 2% before surgery. Standard preoperative prepa-ration with 5% povidone iodine was performed. The eyelidsand eyelashes were covered with a sterile drape. Aftermechanical debridement of corneal epithelium over thecentral 9—10 mm, 0,1% Riboflavin in 20% dextran solution(Ricrolin, Sooft, Montegiorgio, Italy) was instilled topicallyevery 2 minutes for 30 minutes. The cornea was exposed toUVA light of 366—374 nm at an irradiance of 3,0 mW/cm2 for30 minutes (Vega CBM-X-Linker, CSO, Florence, Italy). Mean-while riboflavin instillation was continued every 2 minutes.At the end of the procedure, antibiotic and corticosteroiddrops were administered and a therapeutic soft contact lenswas placed on the cornea. Contact lens was removed follow-ing epithelial healing. Antibiotic drops were continued for1 week. Corticosteroid drops were gradually tapered after1 week, and stopped at postoperative first month follow-up

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gen crosslinking with epithelium-off crosslinking in

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visit.Same surgical procedures were performed for TE-CXL,

but the corneal epithelium was not removed. Besides a spe-cial solution of riboflavin 0,1% in 15% dextran, containing

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Table 1 Preoperative comparison of transepithelial corneal coing (Epi-off CXL) groups, in terms of patient characteristics and

Mean ± S.D. (range) TE-CXL (n = 17)

Age (years) 27.35 ± 5.95 (17—3Gender (male/total) 8/17

Follow-up time (months) 22.12 ± 7.61 (12—3UCVA (logMar) 0.80 ± 0.37 (0.16 ±BSCVA (logMar) 0.43 ± 0.31 (0.09—Max cone Apex curvature (diopters) 51.62 ± 5.84 (46.8—Irregularity index 5.28 ± 2.03 (2.6—8CCT (�m) 470.24 ± 38.04 (40

UCVA: uncorrected visual acuity; BSCVA: best spectacle corrected visuaa t-test, Mann-Whitney U test.

PRESS3

iboflavin penetration enhancers such as sodium EDTA,romethamine, and bihydrate sodium phosphate (RicrolinE, Sooft, Montegiorgio, Italy) was used. Outcome measurest baseline and postoperative follow-up visits were reviewedrom patient charts and prepared for statistical analysis.

tatistical analysis

ntra-group comparison of multiple related samples was per-ormed with Friedman ANOVA test. Comparison of relatedwo samples was performed with paired two-sample t-testn case of normal distribution, and with Wilcoxon matchedairs test in the absence of normal distribution. Inter-groupomparisons were performed with t-test in case of normalistribution, and Mann-Whitney U test was used if there isot normal distribution. Two tailed distribution outcomesere accepted for P values. All analyses were performedith Statplus software (Analysoft, USA). P values < 0.05 wereonsidered to be statistically significant.

esults

hirty-six eyes of 36 patients were included in the study.haracteristics of patients before surgery are shown inable 1. Seventeen eyes were recruited in TE-CXL group,nd 19 in epi-off CXL. There was no statistically significantifference between two groups at baseline in terms of demo-raphic, refractive and corneal parameters (Table 1).

Refractive and corneal parameters of TE-CXL group athe baseline and during postoperative follow-up are pre-ented in Table 2. Statistically significant deterioration wasbserved in mean keratometric value (K), maximum ker-tometric value (Kmax), maximum cone apex curvatureapical K) and corneal central thickness (CCT) measurementsP = 0.0023, 0.0025, 0.0001 and 0.0042, respectively). Thereas no statistically significant change in BSCVA, sphericalquivalent of refractive error, and minimum keratomet-ic value (Kmin) measurements (P = 0.5, 0.16 and 0.06,espectively). A slight improvement was observed in central

al. Comparison of transepithelial corneal colla-progressive keratoconus. J Fr Ophtalmol (2014),

orneal astigmatism and irregularity index of central 3 mmP = 0.014 and 0.0091).

In epi-off CXL group, statistically significant improvementas observed in mean K, Kmax, apical K, and central corneal

llagen crosslinking (TE-CXL) and epithelium-off crosslink- refractive-topographical parameters.

Epi-off CXL (n = 19) P valuea

4) 27.16 ± 2.46 (24—34) 0.26069/19 0.6912

6) 17.47 ± 6.79 (12—31) 0.0900 1.30) 0.65 ± 0.38 (0.15—1.30) 0.23171.30) 0.41 ± 0.40 (0.05—1.30) 0.447066) 52.02 ± 4.07 (45—59.5) 0.3338

.6) 4.78 ± 1.66 (1.7—8) 0.42388—532) 481.26 ± 27.42 (446—530) 0.3217

l acuity; CCT: central corneal thickness

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Table 2 Preoperative and postoperative refractive and topographical data in transepithelial corneal collagen crosslink-ing group.

Mean ± S.D. (range) Preoperative 3 months 6 months 12 months Last visit P valuea

UCVA (logMar) 0.80 ± 0.37 0.71 ± 0.38 0.83 ± 0.38 0.8 ± 0.39 0.88 ± 0.44 0.0345BSCVA (logMar) 0.43 ± 0.31 0.41 ± 0.33 0.43 ± 0.36 0.45 ± 0.40 0.43 ± 0.41 0.5370Spherical equivalent (D) −5.46 ± 3.75 −5.35 ± 4.00 −5.07 ± 4.15 −5.38 ± 3.40 −6.27 ± 4.46 0.1635Mean K (D) 47.47 ± 5.96 47.42 ± 5.57 47.72 ± 5.63 48.35 ± 5.63 48.18 ± 5.40 0.0023Kmin (D) 45.99 ± 5.35 46.46 ± 4.86 46.55 ± 4.82 47.48 ± 5.05 46.72 ± 4.54 0.0670Kmax (D) 48.75 ± 6.82 49.36 ± 6.76 49 ± 6.58 50.57 ± 6.82 49.66 ± 6.30 0.0025Astigmatism (D) 2.82 ± 1.92 2.91 ± 2.12 2.49 ± 2.25 3.15 ± 2.00 2.63 ± 2.46 0.0144Irregularity index 5.25 ± 2.02 4.71 ± 1.93 5.11 ± 1.66 5.44 ± 1.65 4.86 ± 1.76 0.0091Max cone apex curvature (D) 51.62 ± 5.84 51.78 ± 5.92 52.40 ± 5.85 53.55 ± 5.97 53.70 ± 5.49 < 0.0001CCT (�m) 470 ± 38 466 ± 44 458 ± 49 446 ± 59 441 ± 54 0.0042

UCVA: uncorrected visual acuity; BSCVA: best spectacle corrected visual acuity; CCT: central corneal thickness; Mean K: meankeratometric value; Kmin: minimum keratometric value; Kmax: maximum keratometric value.a

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Friedman ANOVA test.

stigmatism (P < 0.0001, P = 0.004, 0.001, 0.003, respec-ively). There was no a statistically significant change inCVA, BSCVA, spherical equivalent, Kmin, and irregularity

ndex of central 3 mm as shown in Table 3 (P = 0.07, 0.14,.4, 0.1, 0.07, respectively).

Postoperative changes of corneal and refractive param-ters were calculated using the difference between theeasurements of last follow-up visit and baseline. The com-arison of postoperative changes between two groups isresented in Table 4. There was no statistically significantifference between postoperative changes of two groups,oncerning BSCVA, spherical equivalent, irregularity index ofentral 3 mm, and CCT. However, epi-off CXL group showedtatistically significantly better outcome in postoperativehanges of corneal parameters such as mean K, apical K,entral corneal astigmatism (P = 0.01, 0.0002, and 0.03,

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gen crosslinking with epithelium-off crosslinking in

http://dx.doi.org/10.1016/j.jfo.2013.11.012

espectively).An increase of ≥ 1D in apical K was observed in two of 19

yes (11%) in epi-off CXL group, and 11 of 17 eyes (65%) in TE-XL group at the last follow-up visit, compared to baseline

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Table 3 Preoperative and postoperative refractive and topogrgroup.

Mean ± S.D. (range) Preoperative 3 months

UCVA (logMar) 0.65 ± 0.38 0.74 ± 0.39

BSCVA (logMar) 0.41 ± 0.40 0.43 ± 0.33

Spherical equivalent (D) −4.00 ± 3.00 −3.86 ± 3.03

Mean K (D) 46.34 ± 3.28 46.74 ± 4.07

Kmin (D) 44.41 ± 3.27 44.95 ± 4.20

Kmax (D) 48.25 ± 3.49 48.61 ± 4.19

Astigmatism (D) 3.88 ± 1.68 3.62 ± 1.76

Irregularity index 4.78 ± 1.66 4.77 ± 1.77

Max cone apex curvature (D) 52.02 ± 4.07 51.67 ± 3.79

CCT (�m) 481 ± 27 443 ± 41

UCVA: uncorrected visual acuity; BSCVA: best spectacle corrected

keratometric value; Kmin: minimum keratometric value; Kmax: maxima Friedman ANOVA test.

P < 0.0001). In epi-off CXL group, apical K decreased in 13yes, and remained unchanged in four eyes. In TE-CXL group,pical K decreased in four eyes, and remained unchangedn two eyes. No postoperative complication was observedn TE-CXL group. Fourteen patients of epi-off CXL grouphowed corneal edema that resolved without haze with top-cal corticosteroid treatment in 4 months.

iscussion

n intact corneal epithelium absorbs 30—33% of UVA irra-iation, and with additional effect of riboflavin in thepithelium, this blockage rate reaches to approximately5%. In addition to UVA blockage, an intact corneal epithe-ium avoids the riboflavin infiltration to corneal stroma,

al. Comparison of transepithelial corneal colla-progressive keratoconus. J Fr Ophtalmol (2014),

ecause of its hydrophilic macromolecular structure. Its reported that, in case of epithelial removal, stromalose of riboflavin reaches a level of a hundred timesf that when epithelium is intact [8,9]. Due to these

aphical data in epithelium-off corneal collagen crosslinking

6 months 12 months Last visit P valuea

0.71 ± 0.40 0.68 ± 0.40 0.67 ± 0.42 0.07450.39 ± 0.27 0.38 ± 0.28 0.37 ± 0.27 0.1499

−3.39 ± 2.51 −3.45 ± 2.41 −3.64 ± 2.49 0.444545.99 ± 3.70 45.98 ± 3.72 46.01 ± 70 < 0.000144.58 ± 4.19 44.57 ± 4.19 44.60 ± 4.17 0.127148.03 ± 3.94 47.98 ± 392 48.00 ± 3.90 0.00373.50 ± 1.64 3.46 ± 1.63 3.45 ± 1.63 0.00344.69 ± 1.62 4.63 ± 1.63 4.63 ± 1.62 0.0736

51.47 ± 3.65 51.28 ± 3.57 51.22 ± 3.51 0.0015448 ± 45 467 ± 30 472 ± 31 < 0.0001

visual acuity; CCT: central corneal thickness; Mean K: meanum keratometric value.

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Transepithelial and epithelium-off crosslinking in keratoconus 5

Table 4 Comparison of postoperative change of refractive and corneal parameters between two study groups. Positivevalues represent an increase and negative values a decrease postoperatively.

Mean ± S.D. (range) TE-CXL(postop—preop)a

Epi-off CXL(postop—preop)a

P valueb

BSCVA (logMar) −0.003 ± 0.21 −0.05 ± 0.26 0.5366Spherical equivalent (D) −0.82 ± 2.02 0.36 ± 1.56 0.1681Mean K (D) 0.71 ± 2.13 −0.33 ± 0.91 0.0118Astigmatism (D) −0.19 ± 1.47 −0.43 ± 0.67 0.0324Max cone apex curvature (D) 2.08 ± 2.49 −0.8 ± 1.03 0.0002Irregularity index −0.42 ± 1.15 −0.15 ± 0.46 0.3729CCT (�m) −29 ± 41 −9 ± 23 0.1885

BSCVA: best spectacle corrected visual acuity; CCT: central corneal thickness; Mean K: mean keratometric value.a The difference of refractive and corneal parameters between postoperative and preoperative measurements.b t-test, Mann-Whitney U test.

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facts, corneal epithelium debridement is an indispens-able part of the standard CXL procedure [4]. However,the removal of epithelium can cause some complicationssuch as severe postoperative pain, temporary visual blur-ring, epithelial healing problems, haze, viral reactivation,even corneal melting. To prevent these serious problems,some researchers have performed a number of studieson a special riboflavin solution, which can penetrate theintact epithelium. In these studies, it has been reportedthat some substances such as benzalkonium chloride, EDTA,and trometamol may enhance the epithelial penetrance ofhydrophilic macromolecules [10—16]. EDTA has an effect ofbreaking intercellular bonds, thus it facilitates epithelialpermeability. Another material, topical anesthetic tetra-caine 1%, is reported to be used for loosening epithelialtight junctions in order to facilitate epithelial permeabil-ity [17]. Based on these findings, transepithelial CXL hasbeen defined for the treatment of progressive keratoconuswithout debridement of corneal epithelium [16—19].

In the present study, we analyzed retrospectively theresults of TE-CXL in 17 eyes and epi-off CXL in 19 eyes.In TE-CXL group, Mean K, Kmax, apical K, and CCT showeddeterioration at the end of the follow-up time (mean ± SD:22,12 ± 7,61 months). However, in epi-off group, statisti-cally significant improvement was observed in mean K,Kmax, apical K, and central corneal astigmatism (meanfollow-up ± SD: 17,47 ± 6,79 months). Mean CCT of epi-offCXL cases decreased at 3rd month of CXL, but then increasedgradually and reached to baseline level finally (Table 3). Thiscan be due to false-thinner measurement of Orbscan II inedematous corneas as we had a high rate of long lastingcorneal edema in epi-off CXL cases. Orbscan pachymetricmeasurement is reported to give thinner results in case ofan obscuring factor such as haze or edema [20]. In our study,ectatic progression continued after CXL in 11% of epi-off CXLcases, and 65% of TE-CXL cases.

There are controversial reports about the efficacy of TE-CXL in the literature. In a recent study, Koppen et al. [16]analyzed the efficacy of TE-CXL in 53 eyes of 38 patients

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with progressive keratoconus. They reported that TE-CXLwas less effective than standard CXL in stabilizing progres-sive disease. Buzzonetti et al. [21] evaluated the results ofTE-CXL in young patients under 18 years, and they concluded

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hat this technique did not effectively halt keratoconus pro-ression in children. However, Filipello et al. [18] reportedhat TE-CXL appeared to stop keratoconus progression with

significant improvement in visual and topographic param-ters in a patient group of 20 keratoconus cases. Similarly,t has been reported that the improvements in topograph-cal parameters provided by TE-CXL were comparable tohose obtained after standard CXL in pediatric keratoconus,n the study of Magli et al. [22]. In another study, Spadeat al. [23] reported that TE-CXL seemed moderately effec-ive in keratoconic eyes with ultrathin corneas (331 to89 �m).

In a confocal microscopy study, Touboul et al. [24] haveompared the early corneal healing process following con-entional, transepithelial, and accelerated CXL protocols.hey have reported that the anterior corneal stroma showedignificant changes following conventional and acceleratedXL in early postoperative period. However, the corneappeared to be unaltered following TE-CXL in confocalicroscopy. This finding may explain the reason for the inef-ciency of TE-CXL that we observed in our study. Recently,

new riboflavin impregnation method has been describedo increase the efficiency of TE-CXL. Bikbova et al. [25]ave used iontophoresis to enhance the transepithelialenetration of riboflavin in 22 eyes of 19 patients with pro-ressive keratoconus. They have reported that TE-CXL byontophoresis appeared to halt progression with a statisti-ally significant improvement in topographic parameters.

In conclusion, although TE-CXL is a safe and comfort-ble procedure, there are conflicting opinions about itsfficacy. Based on our results, TE-CXL does not effec-ively halt the progression of keratoconus. However, thisonclusion should be interpreted with caution due to themall number of patients, limited follow-up period, andotential biases related to the retrospective nature of ourtudy.

al. Comparison of transepithelial corneal colla-progressive keratoconus. J Fr Ophtalmol (2014),

isclosure of interest

he authors declare that they have no conflict of interestoncerning this article.

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gen crosslinking with epithelium-off crosslinking in

http://dx.doi.org/10.1016/j.jfo.2013.11.012

Exp Eye Res 2000;71:3—10.13] Majumdar S, Hippalgaonkar K, Repka MA. Effect of chitosan,

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