safety and efficacy of tacrolimus ointment 0.1% (protopic™) in atopic dermatitis: a canadian...

Safety and Efficacy of TacrolimusOintment 0.1% (ProtopicTM) inAtopic Dermatitis: A CanadianOpen-Label Multicenter Study

Jerry Tan1 and Richard Langley2

Abstract

Background: Most previously published trials of topical tacrolimus in atopicdermatitis were of relatively short duration and comprised a limited population withmoderate-to-severe disease.

Objective: The goal of the study was to evaluate the safety and efficacy over a 6-monthperiod of tacrolimus 0.1% ointment in children and adults with a broader severityspectrum of atopic dermatitis.

Methods: An open-label multicenter trial in patients 2 years and older was used.Primary safety and tolerability assessments included skin infection and application siteadverse events. Efficacy parameters were body surface area involvement, pruritus score,and overall reponse.

Results: There were 240 patients recruited at 23 study sites. Significant improvementfrom baseline was noted for all efficacy endpoints in both pediatric and adult patients. Skininfections occurred in 26% of patients. Burning sensation with product application, re-ported by 38% of patients, was transient and of mild-to-moderate severity in the majority.

Conclusion: Tacrolimus 0.1% ointment was safe, well tolerated, and efficacious intreatment of atopic dermatitis in children and adults over six months.

Sommaire

Antecedents: Les essais anterieurs sur I’effet du tacrolimus topique sur la dermatiteatopique etaient relativement de courte duree et impliquait des sujets souffrant d’uneforme moderee a grave de la maladie.

Objectif: Evaluer I’innocuite et I’efficacite de I’onguent tacrolimus a 0.1% chez lesenfants et les adultes souffrant de divers degres de dermatite atopique.

Methodes: Une etude ouverte multicentrique a ete menee sur des patients ages de 2ans et plus. Les principaux criteres permettant de mesurer I’innocuite du traitement et latolerance du patient comprenaient les infections cutanees et les evenements indesirablesau site de I’application. Les parametres d’efficacite etaient les surfaces atteintes, le scorede prurit et la reaction generale.

Resultats: Deux cent quarante patients recrutes de 23 centres ont participe a I’etude.Des ameliorations considerables par rapport a la condition de base ont ete notees aupoint de vue de I’efficaeite, tant chez les patients pediatriques qu’adultes. Des infectionscutanees se sont produites chez 26% des patients. Des sensations de brulure au momentde I’application, passageres et pour la plupart douces a moderees, ont ete ressenties par38% des patients.

Conclusion: L’innocuite de I’onguent tacrolimus a 0.1%, la tolerance des patients a cetraitement ainsi que son efficacite au cours de six mois ont ete prouvees dans le traite-ment des dermatites atopiques chez les enfants et les adultes.

1Department of Medicine, University of Western Ontario, Windsor, Ontario, Canada2Department of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada

Online publication: 2 December 2004

Presented in part as an oral presentation at Canadian Dermatology Association Annual Meeting, Ottawa, Ontario, Canada, July 1, 2003.

Correspondence to: Jerry Tan, Windsor Clinical Research Inc., 2224 Walker Road, Suite 300, Windsor, Ontario, N8W 5L7, Canada. E-mail: [email protected]

DOI: 10.1007/s10227-003-0115-zJ Cutan Med Surg 2004; 213–219

213

Tacrolimus, a calcineurin inhibitor that suppresses T-cell activation and proliferation, was approved in

Canada in 2001 as an ointment preparation in concen-trations of 0.03% and 0.1% for the treatment of atopicdermatitis (AD). Previous randomized placebo-con-trolled trials conducted in the US with topical tacrolimusdemonstrated the efficacy and safety of this agent in thetreatment of moderate-to-severe AD in adults1,2 andchildren aged 2–15.3 These pivotal studies comprised astrictly defined subset of moderate-to-severe AD patients.Additionally the studies were of relatively short duration(12 weeks), and long-term open-label extension studydata were unavailable at the time of planning this study.In view of the variability of disease manifestation and thechronic nature of the condition, longer-term studies onsafety and durability of efficacy responses were war-ranted. We initiated a Canada-wide multicenter study toevaluate the safety and efficacy of tacrolimus 0.1% oint-ment in a broader-based patient population than thoseenrolled in the pivotal clinical trials. We included a widespectrum of patients with AD for whom an alternative toconventional therapies may be beneficial. We report thelargest Canadian study of atopic dermatitis patientstreated with topical tacrolimus.

Methods

Study DesignThis open-label, 6-month, noncomparative study wasconducted at 23 centers between October 2000 andMarch 2002. For each site, Ethics Review Board approvalwas obtained before the study commenced. The parentsor guardians of all patients gave informed consent and,when age-appropriate, the patients gave assent beforeenrollment in the study.

Patient SelectionMale and female patients aged 2 years and older with ADwhom the investigator judged could benefit from analternative to conventional treatment, except for thosewho had previously participated in a tacrolimus study,were considered for entry into the trial. Atopic dermatitisseverity was graded by the criteria of Rajka and Lange-land.4 Inclusion criteria also involved willingness (patientor guardian) to give voluntary, written informed consentand to comply with medication washout and followup.Females of childbearing potential and sexually activemales were required to use effective birth control meth-ods during the study.

Excluded from the study were patients with skindisorders other than AD in the affected area; those withknown hypersensitivity to macrolides or to excipients ofthe ointment; those with a systemic disease such as canceror HIV; and those with chronic systemic conditions thatwere not well controlled. Pregnant and breast-feedingwomen were also excluded.

Treatment PlanBefore starting the study drug, patients were required toundergo washout periods of the following treatments asshown in parentheses, and use of these agents was alsoprohibited during the study: topical corticosteroids andother topical agents applied to the AD-affected area suchas anesthetics, creams, lotions (1 day); topical antihista-mines and topical antimicrobials (1 week); systemic cor-ticosteroids, nonsteroidal immunosuppressants, UVA orUVB light treatments, or investigational drugs (4 weeks).During the study systemic corticosteroids were permittedfor conditions other than AD, and inhaled/intranasalcorticosteroids or systemic anti-infective therapy couldbe administered if required. Oral antihistamines werepermitted at the investigator’s discretion. Sunscreenscould be applied to lesions as required.

Patients received treatment with tacrolimus ointment(Protopic�) 0.1 % twice daily, with 10–14 h betweenapplications. The ointment was applied as a thin coat tothe affected area(s). Treatment continued while diseasewas present and for 1 week after resolution, or as directedby the investigator. The presenting episode (study entry)and any subsequent episodes during the 6-month studyperiod were treated.

OutcomesPatients were assessed at 2 weeks and at 1, 2, 3, and 6months after study entry. The primary outcome ofinterest was the safety profile of 0.1 % tacrolimus oint-ment in our broad-based study population. Adverseevents, whether reported spontaneously by the patientsor observed by the investigators, were categorized asbeing application site–related or not, and coded using theMedDRA dictionary. Growth, as reflected by changes inheight and weight, was also assessed in the pediatricpopulation over the course of the study.

In addition to the safety analysis, efficacy was evalu-ated during the visits by body surface area (BSA)involvement, pruritus score, and overall response:

Affected BSA was estimated by the investigator as theaffected percentage of each of head/neck, upper limbs,trunk, and lower limbs. From these estimates the overallpercentage affected BSA was derived according to therule of 9’s with BSA = (Head/neck * 9%) + (Upper Limbs* 18%) + (Trunk * 37%) + (Lower limbs * 36%).

Pruritus was scored by the patient or guardian on a75-mm visual analog scale anchored by ‘‘No itch’’ and‘‘Worst itch imaginable.’’

Overall response was rated by the patient or guardianon a 7-point Likert scale, ranging from ‘‘much better’’being the best response to ‘‘much worse’’ being the worst.

Statistical AnalysisAll patients who had applied the study ointment at leastonce were included in the analyses (intent-to-treat ap-proach). The data treatment was primarily descriptive.For height and weight changes, percentage of body sur-

214 Journal of Cutaneous Medicine and Surgery Volume 8 Number 4 August 2004

face area affected, and intensity of itch, the statisticalsignificance of changes from baseline at each post-base-line visit was evaluated by the paired t-test. These anal-yses also were performed in the following subgroups ofpatients:

Disease severity (at baseline): mild vs. moderate vs.severeAge group: pediatric (15 years and under) vs. adult(16 years and above)Disease severity (at baseline) and age group: overallresponse variable only

Results

Study PopulationAt the 23 study centers, 240 patients were enrolled, ofwhom 236 received at least one application of tacrolimus0.1% ointment. Patients ranged in age from 2 to72 years; about one third (82/236) were pediatric (2–15 years). The baseline characteristics of the study pop-ulation are presented in Table I. Baseline disease severityis shown, by age group, in Figure 1. There were 48withdrawals prior to study completion. The most fre-quently cited reasons for discontinuation (more than 1reason could be given) were insufficient efficacy (14 of236 patients, 5.9%), loss to followup (12/236, 5.4%), andnoncompliance (10/236, 4.2%).

Adverse EventsSkin Infections occurred in 26% of the study population(61 patients); 20% of patients had infections at theapplication site and 9% reported nonapplication siteinfections. Table II provides a summary of skin infectionsthat occurred most often in the pediatric and adultpopulations. Overall, 32% of children and 23% of adultshad at least one skin infection. The major differencesbetween adults and children in frequency of skin infec-tions were folliculitis and application site pustules, whichwere more frequent among the adults, and impetigo,which occurred more often in children. In addition to theinfections summarized in Table II, there were singleoccurrences of varicella (in a 4 year old), tinea pedis (inan adult), pityriasis rosea (in an 11 year old), and con-dyloma acuminatum (in an adult). The majority ofcutaneous infections were graded mild or moderate inseverity.

Application site adverse events that occurred most fre-quently (more than 5% of patients) are shown in Ta-ble III. Burning sensation with medication application,reported in 38% of patients, was graded as mild in 18%(42 of 236 patients), moderate in 14% (33/236), and se-vere in 6% (15/236). Burning occurred transiently; itsprevalence was highest within the first 2 weeks of treat-ment but diminished to approximately 5% for theremainder of the study. The duration of burning wasgreatest in patients whose disease was most severe atbaseline.

Nonapplication site adverse events were reported by 72%of patients over the course of the study. Most of theseevents occurred in fewer than 5% of patients except fornasopharyngitis (21.2%), headache (16.9%), influenza(8.1%), or influenza-like illness (5.1%), and pharyngitis(5.9%). There were no reported malignancies. Overall,the severity of nonapplication site adverse events wasmost often rated mild or moderate.

Eight patients cited adverse events as reasons forstudy discontinuation, either as the sole reason or incombination with other factors. Five of these adverseevents involved the application site and were judged bythe investigators to be possibly or probably treatment-related. All adverse events associated with discontinua-tion are shown in Table IV.

TABLE I

Description of study population

N = 236

Patient characteristics at baseline Mean value (±SD) % of total

Age in years:2–15 years = 82 7.7 (±3.4) 34.7‡16 years = 154 32.7 (±13.2) 65.3Sex (Male:Female) 100:136 42:58Race (Caucasian:Asian:Other) 169:38:29 72:16:12

Number of patients % of totalSeverity of atopic dermatitisa

Mild 13 5.5Moderate 128 54.2Severe 95 40.3

aRajka and Langeland criteria4: Extent, course, and intensity each scoredas 1 (mildest), 3 (most severe), or intermediate scores of 1.5, 2, 2.5.Extent: <approximately 9% of body area = 1; more than approximately36% of body area = 3. Course: >3 months of remission during a year = 1;continuous course = 3. Intensity: Mild itch, only exceptionally dis-turbing night sleep = 1; severe itch usually disturbing sleep = 3. Severity= sum of extent, course, and intensity scores. Mild = score of 3–4,moderate = 4.5–7.5, severe = 8–9.

FIGURE 1 Baseline disease severity, by age group.

J. Tan and R. Langley Tacrolimus Ointment in Atopic Dermatitis 215

Four study patients were hospitalized:

� A 7-year-old girl developed cellulitis and discontinuedthe study. She was treated with antibiotics (Staphylo-coccus aureus was cultured), subsequently hospitalized,and recovered fully.

� A 10-year-old boy was hospitalized on two occasionsfor severely infected AD. This patient also had beenreported to have impetigo intermittently during thestudy. Cultures were positive for Staphylococcus. Thepatient recovered and completed the study.

� A 34-year-old man with a history of asthma washospitalized with pneumonia. He recovered and com-pleted the study.

� A 55-year-old man was hospitalized because of septicarthritis, followed by phlebitis, after elective arthroscopyof the knee; he recovered but discontinued the study.

In the pediatric group, no evidence of growth retardationwas observed during the treatment period.

EfficacySignificant improvement from baseline was noted for allefficacy endpoints in both age groups.

BSA Affected

At baseline, the mean percentage of the whole BSAaffected was 29%, which was approximately evenly dis-

tributed across all body sites. The percentage-affectedBSA decreased rapidly and was sustained, occurring mostdramatically during the first month after starting treat-ment and then progressively declining to a mean BSA of7% at the end of the study (reduction of 75% frombaseline). The change from baseline in affected BSA washighly statistically significant (p < 0.0001) at each of theevaluation times. Pediatric patients tended to improve toa greater extent than adults; the change from baselineattained statistical significance at week 2 and month 3 (p <0.05) (Fig. 2).

Pruritus

Baseline scores for pruritus ranged from a minimumof 0 mm to the maximum 75 mm on the visual analogscale (VAS); the mean baseline value was 42 mm. Themean score had decreased by 33% to 28 mm by week 2,and thereafter (months 1, 2, 3, and 6) remained stable ataround 20 mm. Pediatric and adult populations re-sponded similarly with respect to pruritus with a trend togreater VAS score improvement in the pediatric age

TABLE II

Skin infections by age group

Incidence of skin infections, n (%)

Pediatrica N = 82 Adultb N = 154

Infection Appl. site Nonappl. site All Appl. site Nonappl. site All All N = 236

Folliculitis 3 (3.7) 2 (2.4) 5 (6.1) 19 (12.3) 1 (0.6) 19 (12.3) 24 (10.2)Impetigo 8 (9.8) 5 (6.1) 11 (13.4) 5 (3.2) 0 (0.0) 5 (3.2) 16 (6.8)Other appl. site infection 5 (6.1) 0 (0.0) 5 (6.1) 5 (3.2) 0 (0.0) 5 (3.2) 10 (4.2)Pustules 0 (0.0) 0 (0.0) 0 (0.0) 5 (3.2) 0 (0.0) 5 (3.2) 5 (2.1)Herpes simplex 1 (1:2) 1 (1.2) 2 (2.4) 0 (0.0) 3 (1.9) 3 (1.9) 5 (2.1)Molluscum contagiosum 0 (0.0) 2 (2.4) 2 (2.4) 1 (0.6) 1 (0.6) 1 (0.6) 3 (1.3)Warts 0 (0.0) 0 (0.0) 0 (0.0) 1 (0.6) 2 (1.3) 3 (1.9) 3 (1.3)Fungal infection 0 (0.0) 1 (1.2) 1 (1.2) 0 (0.0) 1 (0.6) 1 (0.6) 2 (0.8)Nail infection 0 (0.0) 1 (1.2) 1 (1.2) 0 (0.0) 1 (0.6) 1 (0.6) 2 (0.8)

aAge = 2–15 years.bage = 16 years and above.

TABLE III

Application site adverse events reported by at least 5% of patients

Patients reporting (N = 236)

Event n %

Burning 90 38.1Pruritus 80 33.9Infection 47 19.9Paresthesia 22 9.3Warmth 12 5.1

TABLE IV

Adverse events associated with study discontinuation

Event Severity Patient age

Burning sensation,application site

Severe 20

Burning, application site Severe 20Itching, application site Severe 72Folliculitis, application

site, andSevere 40

Sweating SevereCellulitis, application site

(lower limbs)Moderate 7

Flare of eczema, total body Severe 8Septic arthritis, knee,

post-arthroscopy followedby phlebitis (hospitalized)

Severe 55

Generalized skin infection Moderate 16


group. The itch scores over time, by baseline AD sever-ity, are shown in Figure 3.

Overall Response

A substantial and rapid clinical improvement wasnoted by patients for all degrees of baseline AD severity.Treatment success, defined as a response of slightlybetter, better, or much better, was achieved by over 80%of patients within the first 2 weeks of starting treatment.The success rate is displayed by baseline disease severityin Figure 4, and Table V displays the treatment successand failure rates by age group. Reported success rates at 4of the 5 observation times were 5–8 percentage pointshigher in the pediatric group than in the adults.

Fourteen patients discontinued the study because of areported lack of efficacy. Evaluation of their overall re-sponse scores, however, demonstrated that 4 of thesepatients reported improvement. Furthermore, 9/14demonstrated improvement in affected BSA and 5/14reported improvement in itch score. Thus, objective andsubjective measures of efficacy did not consistently cor-respond to reported lack of efficacy.

Discussion

Although topical corticosteroids have been the corner-stone of treatment for atopic dermatitis over the past

40 years, there is a paucity of both high-quality, double-blind, placebo-controlled, randomized trials with theseagents exceeding one month’s duration and safety studieswith long-term use.5 In contrast, the recent advent of thetopical immunomodulators tacrolimus and pimecrolimusfor atopic dermatitis has compelled the development ofclinical studies to substantiate both short- and long-termefficacy and ongoing safety.

Tacrolimus ointment 0.03% and 0.1% has been ap-proved in Canada for treatment of atopic dermatitis.While both the 0.1% and 0.03% concentrations weredemonstrated in pivotal trials to be efficacious and safe inthe treatment of atopic dermatitis in childen aged 2–15,3

in adults, the 0.1% concentration was significantly moreefficacious than 0.03%.1 The safety of the 0.1% ointmentformulation in children aged 2–15 years was demon-strated in a long-term open-label study of up to 12months in which there was no increased incidence ofinfections or other significant adverse events.6 Accord-ingly, tacrolimus 0.1 % ointment was selected in thisstudy to facilitate treatment of both children and adultsand to approximate clinical practice. It differs from the

FIGURE 2 Change in body surface area affected, by age group.

FIGURE 3 Change in itch intensity, by baseline disease severity.

FIGURE 4 Overall response, by baseline disease severity.

TABLE V

Success and failure rates based on overall response scores

Over all response Number (%) ofpatients

Age groupa Study period Successb Failure Total

Pediatric Week 2 75 (92.6) 6 (7.4) 81Month 1 77 (96.3) 3 (3.8) 80Month 2 72 (93.5) 5 (6.5) 77Month 3 65 (86.7) 10 (13.3) 75Month 6 67 (93.1) 5 (6.9) 72

Adult Week 2 126 (85.1) 22 (14.9) 148Month 1 130 (90.9) 13 (9.1) 143Month 2 122 (90.4) 13 (9.6) 135Month 3 116 (89.9) 13 (10.1) 129Month 6 104 (87.4) 15 (12.6) 119

aPediatric = 2–15 years; adult = 16 years and above.bSuccess was defined as an overall response score of slightly better,better, or much better.


published pivotal placebo-controlled clinical trials 1–3 notonly by its longer (6 month) duration, but also by itsinclusion of both pediatric and adult patients who had awide range of disease severity. Thus, we were able toevaluate safety and tolerability under more typical con-ditions and to explore the relative frequency of adverseevents and efficacy outcomes for these subgroups.

The immunornodulatory effects of tacrolimus could,in theory, increase the risk of cutaneous infections whenused long term to treat chronic conditions such as atopicdermatitis. Since systemic absorption following topicalapplication is undetectable or very low7 the theoreticalissue of concern is application site infection. However,we did not observe an increase in incidence of skininfections at the application site or elsewhere that wouldsupport this concern.

In three 12-week controlled studies (two adult, onepediatric), the overall rates of cutaneous infections were19% and 20% for patients treated with vehicle or ta-crolimus 0.1%, respectively.1–3 In the two long-termopen-label studies of up to 1 year duration with tacroli-mus 0.1% in children (2–15 years) and adults (‡18 years),overall cutaneous infection rates of 32%6 and 37%,8

respectively, were reported in the original publication orin a subsequent analysis.9 The overall cutaneous infectionrate of 26% in the current study is, therefore, consistentwith a trial duration intermediate between these pivotalshort-term and open-label long-term studies. The ratesof infection in the pediatric and adult open-label studieswere also similar to that observed in the current study(respectively 2%, 11%, 10% for folliculitis; 6%, 2%, 1%for dermatophytosis; 5%, 13%, 2% for herpes simplex;2%, 1%, 1% for mollusca; and 3%, 2%, 1% for warts).

In this study folliculitis developed in 12.3% of adultsand 6.3% of children. The etiology, i.e., infective orocclusional, is unclear as cultures were not routinelyperformed. An age-related differential in incidence offolliculitis was also noted by Fleischer et al.9 in thepooled analysis of two long-term studies: Folliculitisoccurred in 11% of adults treated with tacrolimus 0.1%ointment compared with 2% in children. The lowerincidence in children may reflect the immaturity ofpilosebaceous structures or the relative difference in skinsurface area between these two groups.

The incidence of burning sensation at the applicationsite was 38% in this study, with a higher rate in adults(49%) than in children (15%). Our results are similar tothose reported in previous long-term studies of 47% inadults8 and 26% in children.6 The reason for this dif-ference in age-related incidence is unclear. Patients withsevere disease or with more than 75% body surface areaaffected had previously been shown to report burningmore frequently than those with less severe disease.2 Inthe present study, patients with more severe disease atbaseline tended to have a longer duration of burning.

While efficacy was a secondary objective in this study,the magnitude of improvement in outcome measure-

ments at 6 months was comparable to those previouslyreported in the pediatric and adult open-label long-termstudies with percentage reduction in pruritus score (50%in pediatric study and 52% in present study); reduction inpercentage body surface area involvement (53% in thepediatric study, 64% in the adult study, 75% in thepresent study); and investigator’s global assessment ofsuccess (93% in adult study, 89% in present study).

Furthermore, this study suggests that the magnitudeof improvement in body surface area affected is greater forchildren than adults. Improvement in all efficacy outcomeparameters was demonstrated for all baseline severitygrades of atopic dermatitis—mild, moderate, and severe.

The data on the 82 children in our study contributesubstantially to the body of knowledge on the use of ta-crolimus ointment 0.1% in children. Kang et al.6 treated255 patients, aged 2–15 years, with atopic dermatitis with0.1% tacrolimus ointment for up to 1 year and found thistreatment to be safe and effective, quite similar to ourown findings.

In summary, this open-label study demonstrates thesafety and efficacy of tacrolimus 0.1% ointment whenused across the severity spectrum of atopic dermatitis inboth children and adults. We have shown, in a typicalCanadian dermatology practice setting, a favorable clin-ical profile over an extended trial duration of 6 months.

Acknowledgments

The authors thank the members of the Canadian Protopic StudyGroup for their contributions to this research: Dr. StewartAdams, University of Calgary, Calgary, Alberta; Dr. RobertBissonnette, Innovaderm Research Inc., Montreal, Quebec; Dr.Thomas Christensen, Victoria, British Columbia; Dr. JoelClaveau, CHUQ, Hopital L’Hotel-Dieu de Quebec, Ste-Foy,Quebec; Dr. David Gratton, International Dermatology Re-search Inc., Montreal, Quebec; Dr. Wayne Gulliver, NewLabClinical Research Inc., St. John’s, Newfoundland; Dr. AdityaGupta, Sunnybrook and Women’s College Health SciencesCentre, Toronto, Ontario; Dr. Vincent Ho, University of BritishColumbia, Vancouver, British Columbia; Dr. Peter Hull,University of Saskatchewan, Saskatoon, Saskatchewan; Dr.Bernice Krafchik, Hospital for Sick Children, Toronto, Ontario;Dr. Gilles Lauzon, University of Alberta, Edmonton, Alberta;Dr. Chuck Lynde, Toronto Western Hospital, Toronto, Ontario;Dr. Danielle Marcoux, University of Montreal, Montreal,Quebec; Dr. Robert Miller, Dalhousie University, Halifax,Nova Scotia; Dr. Eileen Murray, University of Manitoba,Winnipeg, Manitoba; Dr. Yves Poulin, Centre de RechercheDermatologique de Quebec Metropolitain, Ste-Foy, Quebec; Dr.Julie Prendiville, University of British Columbia, Vancouver,British Columbia; Dr. Neil Shear, University of Toronto, Tor-onto, Ontario; Dr. Kevin Smith, Greater Niagara GeneralHospital, Niagara Falls, Ontario; Ontario; Dr. John Toole,Derm Advances, Winnipeg, Manitoba; Dr. Catherine Zip,University of Calgary, Calgary, Alberta. The authors also


acknowledge the assistance of: Fujisawa Canada Inc., Markham,Ontario, for financial support; Miklos Schulz, PhD, for statisticalsupport; Martha Watson, for editorial support.

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