Topical Luliconazole Research Articles

Case of tinea corporis caused by a terbinafine-sensitive Trichophyton indotineae strain in a Vietnamese worker in Japan.

A 42-year-old Vietnamese egg factory worker in Ishikawa prefecture, Japan, presented with itchy concentric erythema on the trunk and left calf. The lesions tested positive by direct potassium hydroxide examination, and two fungal strains were isolated. The isolates produced conidia abundantly and were morphologically indistinguishable from Trichophyton mentagrophytes/interdigitale, but were identified as Trichophyton indotineae by internal transcribed spacer sequence of ribosomal DNA. The lesions were refractory to treatment with topical luliconazole (LLCZ) cream for 4 weeks but subsided with oral itraconazole (ITCZ) 100 mg/day for 4 weeks in combination with topical lanoconazole (LCZ) cream. The lesions recurred 6 weeks after discontinuation of oral ITCZ, and an additional isolate was cultured. The minimum inhibitory concentrations of antimycotics for the isolate cultured at the first visit were: terbinafine (TBF) 0.03 μg/mL, ITCZ 0.015 μg/mL, LLCZ 0.0005 μg/mL, and LCZ 0.002 μg/mL. No TBF-resistant mutation in the amino acid sequence of squalene epoxidase, i.e., Leu 393 Ser/Phe or Phe 397 Leu, was detected in the isolate. The reason for recalcitrance in this case, despite the isolate's sensitivity to antimycotics, was unclear. Possible factors include insufficient use of the antimycotics, incomplete removal of abundantly produced conidia from the lesions, the patient's environment, and a language gap between the patient and physician hindering communication.

Dermatophytomas in Onychomycosis: A Scoping Review of Prevalence, Diagnosis, and Treatment.

Dermatophytoma, also described as a longitudinal streak/spike, is a form of onychomycosis that presents as yellow/white streaks or patches in the subungual space, with dense fungal masses encased in biofilm. This scoping review of the literature was conducted to address a general lack of information about the epidemiology, pathophysiology, and treatment of dermatophytomas in onychomycosis. A search was performed in the PubMed and Embase databases for the terms "longitudinal spike" or "dermatophytoma." Outcomes of interest were definition, prevalence, methods used for diagnosis, treatments, and treatment efficacy. Inclusion and exclusion of search results required agreement between two independent reviewers. Of a total of 51 records, 37 were included. Two reports provided the first unique definitions/clinical features of dermatophytomas. Overall, many descriptions were found, but one conclusive definition was lacking. Prevalence data were limited and inconsistent. The most frequently mentioned diagnostic techniques were clinical assessment, potassium hydroxide/microscopy, and fungal culture/mycology. Oral terbinafine and topical efinaconazole 10% were the most frequently mentioned treatments, followed by topical luliconazole 5% and other oral treatments (itraconazole, fluconazole, fosravuconazole). In studies with five or more patients without nail excision, cure rates were highest with efinaconazole 10%, which ranged from 41% to 100% depending on the clinical and/or mycologic assessment evaluated. Other drugs with greater than or equal to 50% cure rates were topical luliconazole 5% (50%), oral fosravuconazole (57%), and oral terbinafine (67%). In studies that combined oral terbinafine treatment with nail excision using surgical or chemical (40% urea) methods, cure rates ranged from 50% to 100%. There is little published information regarding dermatophytomas in onychomycosis. More clinical research and physician education are needed. Although dermatophytomas have historically been considered difficult to treat, the efficacy data gathered in this scoping review have demonstrated that newer topical treatments are effective, as are oral antifungals in combination with chemical or surgical methods.

Evaluation of the benefit of the addition of 1% topical luliconazole versus topical bland emollient to the systemic itraconazole therapy for the management of disseminated dermatophytosis: A randomised control trial

AbstractBackgroundThe present epidemic of dermatophytosis in India is marked by an increase in chronic, recurrent and disseminated cases. A combination of oral itraconazole and topical luliconazole is being increasingly utilised by dermatologists in India. The superiority of this combination is not supported by robust clinical trial data.ObjectiveWe conducted this randomised, open‐label, two arms, parallel assignment intervention trial between November 2022 and May 2023 to determine the superiority of topical 1% Luliconazole over bland emollient as adjuvant to systemic Itraconazole therapy in the management of dermatophytosis.MethodIn this study, 135 patients of either sex were randomised to two study cohorts. Major exclusions being concomitant medical illness, use of concomitant medication and substance abuse. Participants were randomly assigned to receive topical bland emollient, (Cohort I, n = 67) or topical luliconazole, (Cohort II, n = 68). Both cohorts received oral itraconazole 200 mg/day (100 mg BID) and levocetirizine 5 mg twice a day as a systemic regime. Clinical and mycological cure at the end of 6 weeks and clinical relapse among cure patients during 10‐week follow‐up were observed.ResultsThe cure rates for Cohorts I and II at 6 weeks were 50 (74.62%) and 56 (82.35%), (p = .46), respectively. During the 4‐week follow‐up period, clinical relapses were observed in 16 (32%) of the 50 patients in Cohort I and 12 (21.43%) of the 56 patients in Cohort II (p = .18). Luliconazole cohort shows a significantly higher medical cost (p < .05).ConclusionOur study shows a similar cure rate and relapse rate for patients receiving topical Luliconazole versus topical bland emollient as an adjuvant to the systemic itraconazole regime.

Comparison of Efficacy between Topical Luliconazole and Topical Clotrimazole in the Treatment of Tinea Corporis and Tinea Cruris

Comparison of Efficacy between Topical Luliconazole and Topical Clotrimazole in the Treatment of Tinea Corporis and Tinea Cruris

Encountering steroid treatment induced tinea incognito: a case report

Tinea incognito refers to a type of dermatophyte infection that affects the skin, and its signs and symptoms upon presentation tend to appear permutated due to the prior use of immunosuppressants, corticosteroids or calcineurin inhibitors. We present a 42-year-old Asian (Indian) male patient with scaly erythematous rashes, mimicking annular erythema, and developing post-corticosteroid usage after an elective hair transplant procedure. The results of the biopsy reported that erythema annulare centrifugum (EAC) was absent, and the sample was suggestive of potential infective folliculitis. By day 3 of the presentation, with fungal stain tested positive for the presence of fungal infection. Based on this, the final diagnosis of tinea incognito was made. The final treatment prescribed for tinea incognito was an anti-fungal tablet of Itraconazole at a dose of 100 mg twice a day for 4 weeks, topical luliconazole, ciclopirox and anti-histamines for itching. Topical corticosteroids can change the clinical appearance of tinea by reducing erythema and scaling while enabling the fungus to grow freely without presenting the typical clinical indications of tinea. Practitioners should follow patients on corticosteroid treatment to alert them to potential cutaneous problems due to possible fungal infections, whenever warranted.

Natural Oil Nanoemulsion-Based Gel Vehicle for Enhancing Antifungal Effect of Topical Luliconazole

Background: Luliconazole, a newer class of imidazole anti-fungal agent, is very effective against several species of fungi, especially dermatophytes. It has very low aqueous solubility acting as barrier for topical delivery and limiting its dermal availability. Aim of the study: This study aimed to formulate luliconazole oil/water nanoemulsion by the aqueous titration method. Methods: Solubility study resulted in selecting peppermint oil, tween 80 and transcutol p as oil phase, surfactant and cosurfactant respectively, although pseudoternary phase diagram construct nanoemulsion area for picking formulations. Fifteen o/w nanoemulsion formulations prepared and characterised for droplet size, polydispersity index, pH values, percent transmittance, luliconazole content. Among formulations, eight preparations introduced to enhance the viscosity of prepared nanoemulsion by combining 0.5% carbopol 934 as gelling agent. Results: The selected preparations demonstrated homogeneous nanoemulgels with pH values appropriate for skin application and accepted luliconazole content. Viscosity results manifested non-newtonian pseudo plastic behavior with shear-thinning viscosity profile. In vitro release studies revealed dissimilar release profile (f2˂50) than that of pure luliconazole dispersion. The results revealed that the formula NG-1 with oil: Smix(2:1):water (15:40:43.5) ratio containing 1% drug and 0.5% carbopol 934 was the optimised formula with excellent spreadability. Conclusion: The study concluded that nanoemulsion-based gel is contemplated an encouraging and proceed technique for the topical preparation and upgrade solubility, dissolution rate and permeability of insufficient water-soluble drugs across the skin.

P111 A case of nail discoloration due to topical treatment of onychomycosis with luliconazole 5% nail solution

Poster session 1, September 21, 2022, 12:30 PM - 1:30 PMWe use efinaconazole 10% topical solution and luliconazole 5% nail solution for topical treatment of onychomycosis in Japan. We show a case of onychomycosis treated with nail debridement and topical luliconazole 5% nail solution to the nail and topical luliconazole 1% cream to the foot. A woman in her seventies with chronic urticaria had a nail spike color change on her left big toe (Fig. 1). We opened the spike lesions with a plastic nipper and KOH direct microscopic examination showed dermatophytoma. We treated with topical luliconazole cream on the toes and soles of the foot and 5% solution on the nail. Because of the summer season, she walked outside in sandals without socks during treatment and noticed the nail yellow color change (Fig. 2). We advised the patient to protect from sun light and not to walk outside without socks. Due to the report from the production company, the reason for nail color change to yellowish is photodegradation of luliconazole. After 1 year since first visit, the fungal infection of the big toe disappeared by our topical treatment. The nail yellow color change also disappeared. We recommended avoiding sunlight exposure on the treated nail during topical treatment of luliconazole 5% nail solution.

ETIOLOGY OF DERMATOPHYTOSIS : A STUDY FROM SOUTH INDIA

BACKGROUND: Dermatophytes are one of the most common fungal agents causing supercial skin infections. The prevalence of these infections varies from place to place and is more commonly associated with low socioeconomic status. AIMS AND OBJECTIVES: To isolate and identify the common dermatophytic species causing the infection and to know the efcacy of the antifungals commonly used against them. METHODS: One hundred and ten new cases, who consented for study were included. Skin scrapings were collected for direct microscopy by KOH and for fungal culture in Sabouraud 4% dextrose agar (SDA) with cycloheximide and dermatophyte test medium. Fungi were identied on the basis of their macroscopic and microscopic features with the help of lactophenol cotton blue staining and urease test. RESULTS: Of the 110 cases, 58 cases were KOH positive for fungal laments and culture positive for dermatophytes. Trichophyton was the predominant isolate (51 cases) with T. verrucosum being the commonest species (28 cases), followed by T. rubrum (16 patients), and T. mentagrophytes (7 cases). All species of Trichophyton were found to be most sensitive to systemic itraconazole and topical luliconazole amongst antifungals. CONCLUSIONS: Trichophyton species is the commonest organism causing fungal infections. Itraconazole and luliconazole are the most effective systemic and topical agents against them.

Comparison of efficacy and safety of topical luliconazole with topical fluconazole against tinea corporis in a tertiary care hospital

Background: Dermatophytosis is a common cutaneous infection worldwide with prevalence varying from 20% to 25%. Luliconazole is a newer topical antifungal applied once daily with greater reservoir property in stratum corneum. Objective of the study was to compare the clinical efficacy and safety of luliconazole 1% cream with Fluconazole 1% cream in patients with mild to severe grades of tinea corporis.Methods: A total of 100 patients with mycologically confirmed tinea corporis were randomised into group A and B respectively. Group A, 50 patients received luliconazole 1% for 2 weeks and group B, 50 patients received fluconazole 1% cream for 4 weeks. Patients were clinically and mycologically evaluated on 0, 2nd and 4th week of treatment and followed up on 8th week for any relapse.Results: Significant improvement in efficacy was seen in Luliconazole while compared with fluconazole group against tinea corporis infection. Mycological cure and clinical improvement showed significant difference in group A. The safety and tolerability profile of both groups were good and statistically comparable.Conclusions: Luliconazole 1% cream is found to be safe, effective and tolerable with low incidence of relapse than fluconazole 1% cream.

Carbon Dioxide Laser Plus Topical 5% Luliconazole: A Better Combination Therapeutic Modality for Onychomycosis.

Background:Onychomycosis has always been a therapeutic challenge because of longer treatment duration, potential adverse effects of oral antifungals, and limited efficacy of topical agents. During the past few years, the emergence of laser therapy has been the topic of discussion as a newer, safe, minimally invasive modality of treatment.Aim:The aim of this study was to evaluate the role of fractional CO2 laser and topical luliconazole 5% lotion in the treatment of onychomycosis, as a combined treatment and as independent modalities.Materials and Methods:This was a prospective, randomized, triple-limb comparative observational study in which 106 patients with KOH and culture-proven onychomycosis were randomly assigned to three groups. Group A received fractional CO2 laser (10,600nm) triweekly for four sessions (0, 3, 9, and 12 weeks) plus topical luliconazole 5.0% lotion applied twice daily on the affected nail plates and nail folds for 12 weeks. Group B received only fractional CO2 with the same frequency of sessions and laser parameters as in group A. Group C received only topical luliconazole 5.0% solution twice daily for 12 weeks. Treatment outcome was evaluated using onychomycosis severity index (OSI) score, mycological parameters, and level of satisfaction of patients.Results:The degree of clinical improvement, mycological cure, and patient’s satisfaction was significantly better in the combined group than individual modalities. There were no severe adverse effects that warranted the discontinuation of the treatment in any of these patients.Conclusion:Fractional CO2 laser combined with topical luliconazole 5% lotion is a safe and effective treatment for onychomycosis especially in those who have contraindications to oral antifungals.

Therapeutic efficacy of topical luliconazole versus topical ketoconazole in the treatment of pityriasis versicolor patients: a hospital based comparative study

<p class="abstract"><strong>Background:</strong> To evaluate the clinical efficacy of 1% topical luliconazole versus 2% topical ketoconazole in pityriasis versicolor patients.</p><p class="abstract"><strong>Methods:</strong> Mycological examination of all the pityriasis versicolor patient was done by using skin scrapings were collected from the skin lesions to prepare for 10% KOH mount, which was examined under the microscope to note the findings as KOH mount positive or negative for Malassezia fungi. KOH mount positive or negative was noted at 0 days, 2 weeks and 4 weeks continued treatments with luliconazole and ketoconazole.<strong></strong></p><p class="abstract"><strong>Results:</strong> At the first days, majorities of patients 46 (92%) of luliconazole group were positive for KOH mount. At 14 days treatment with luliconazole, patients had 11 (22%) positive for KOH mount. At the 28 days treatment with luliconazole, only 2 (4%) patients were positive and most of the patients 49 (98%) were negative for KOH mount. Similarly, in ketoconazole group patients, 47 (94%) patients were positive for KOH mount in beginning of treatment. At 14 days treatment with ketoconazole 16 (32%) patients were positive and 34 (68%) patients were negative for KOH mount. And at the 28 days with treatment of ketoconazole 13 (26%) patients were positive and most of the patients 37 (74%) were negative for ketoconazole.</p><p><strong>Conclusions:</strong> Male population as well as age 26-35 years were more prone for pityriasis versicolor infection. On two weeks of treatment luliconazole and ketoconazole had near about similar efficacy against pityriasis versicolor. But, on continue 4 weeks of treatment regimens topical luliconazole had more clinically efficacious than ketoconazole against pityriasis versicolor.</p>

Efficacy, Safety, and Cost Evaluation of the Topical Luliconazole Therapy versus Topical Clotrimazole Therapy in Patients with Localized Dermatophytosis in a Tertiary Care Hospital: An Observational Study.

Background:Dermatophytosis is a superficial fungal infection that has high affinity for keratinized tissues of the body. The treatment of localized dermatophytosis is a major concern for the dermatologist especially in tropical countries like India. Various topical antifungals are available for the treatment of localized uncomplicated dermatophytosis. Luliconazole is an azole antifungal available that has potent activity against dermatophytes.Objectives:The objective of this study was to compare two treatment modalities for the treatment of localized dermatophytosis in terms of efficacy, safety, and cost evaluation.Materials and Methods:This was a prospective and observational study carried out for 6 months and included 200 patients (luliconazole group [n = 94] and clotrimazole group [n = 106]). Patients were followed up for 2, 4, and 6 weeks. Outcome parameters such as pruritis, erythema, scaling, vesiculations, and global assessment score were noted at 2, 4, and 6 weeks for the assessment of efficacy. The statistical analysis was done using Chi-square and Student's t-test.Results:Luliconazole and clotrimazole showed 56.38% and 23.58% cure rate at the end of two weeks respectively (P < 0.05). At the end of treatment, the cure rates were 98.93% and 95.28% in luliconazole and clotrimazole, respectively (P > 0.005). Both the drugs were equally safe. On cost-effective analysis, luliconazole was found to be more cost-effective than clotrimazole at the end of 2 weeks.Conclusion: Therapeutic efficacy of luliconazole was more as significant proportion of patients achieved complete clearance of lesions at faster rate within 2 weeks with convenient once daily application.

Efficacy of 1% terbinafine and 1% luliconazole in the management of tinea corporis and tinea cruris

Background: Tinea or dermatophytosis is a fungal infection that commonly affects stratum corneum of the skin and its other appendages. Topical antifungal agents are the first-line treatment choice for dermatophytosis among them terbinafine, luliconazole, amorolfine, and sertaconazole are more effective. Aim and Objective: The aim of the study was to assess the efficacy and safety of topical luliconazole with topical terbinafine in tinea corporis and tinea cruris management. Materials and Methods: Study conducted on 180 cases diagnosed clinically and confirmed mycologically with tinea cruris and tinea corpis between age group of 21 and 60 years were recruited. Study consists of two groups, that is, Group 1 administered with 1% terbinafine and Group 2 with 1% luliconazole. Clinical signs such as pruritus, erythema, scaling and mycological culture, and KOH mount were assessed at the beginning, end of 1st, 2nd, and 4th weeks. Results: The comparison of mean pruritus score at the beginning, at the end of 1st week and 2nd week was statistically significant (P < 0.05). The mean erythema score was statistically significant between two study groups from the beginning to the 4th week. The reduction of mean scaling score was statistically significant at the end of 1st week. The KOH values between two study groups showed significant difference at the end of the 1st week (P = 0.028). Conclusion: The status of clinical signs, mycological culture, and KOH values was better in Group 1 than Group 2. Hence, 1% luliconazole is more efficacious than 1% terbinafine in the management of tinea corporis and tinea cruris for 2 weeks.

Viability of pathogenic dermatophytes during a 4-week treatment with 1% topical luliconazole for tinea pedis.

The viability of pathogenic fungi in the scale was investigated during topical administration of 1% luliconazole (LLCZ). Thirteen tinea pedis patients found to be positive on KOH examination were assessed by mycological examinations and quantitative real-time polymerase chain reaction (PCR) targeted internal transcribed spacer (ITS) in ribosomal RNA gene at the initial visit and after 2 and 4 weeks of treatment. Assays showed that the average copy number of ITS DNA had significantly decreased to 22.9% at 2 weeks and 4.8% at 4 weeks compared with the initial visit. LLCZ topical treatment could defeat almost pathogenic dermatophytes in the scales within 4 weeks.

Preparation of luliconazole nanocrystals loaded hydrogel for improvement of dissolution and antifungal activity

Superficial fungal infection in immunocompromised patients can lead to many disorders and complications. Currently, new topical treatment options are critically needed to treat these fungal infections. Luliconazole (LZL) is a topical antifungal medicine used for fungal infection treatment. The purpose of this paper was to develop a new topical luliconazole nanocrystal (LNC) incorporated hydrogel. This study suggested the potential benefits of LNC embedded in a gel as a drug delivery system for topical antifungal treatments. Preliminary experiments were therefore carried out to characterize the LNC in comparison with raw drug. Prepared gel was homogeneous for human use with about 88 percent trapping, non-irritant and safe. Nano-systems showed an overall 5 fold enhancement in solubility, 4 fold increase in dissolution velocity, higher skin retention and better antifungal activity. Drugs retained from LNC hydrogel (N-GEL) in different skin layers within 8 h were the highest, i.e. 62.17% compared to coarse suspension (41.87%), nanosuspension (49.77%), D-GEL (55.76%). In addition, LNC and N-GEL had higher ZOI (41.20 ± 0.61mm and 44.25 ± 0.57mm respectively) than LZL and D-GEL (35.98 ± 0.81mm and 36.83 ± 0.83mm respectively). Therefore, it was observed that LNC loaded hydrogel was more effective in killing the fungus. Consequently, hydrogel incorporated with LNC could be a new approach with improved activity and increased dermal delivery for drugs with poor aqueous solubility rather than coarse drug containing gel.

A randomized comparative study to assess the efficacy of topical luliconazole versus topical clotrimazole in tinea corporis and tinea cruris

Background: Dermatophytosis is a common cutaneous infection in India with prevalence varying from 36.6% to 78.4%. Topical azoles and allylamines are used to treat localized dermatophytosis but has disadvantages such as long duration of therapy, poor compliance, and high relapse rate. Luliconazole is a newer topical imidazole antifungal applied once daily with greater reservoir property in stratum corneum. Aims and Objective: The aim of the study was to compare the efficacy of topical luliconazole versus topical clotrimazole in tinea corporis and tinea cruris. Materials and Methods: An open-labeled randomized comparative study in the Dermatology Outpatient Department of Tirunelveli Medical College done from September 2015 to September 2016. Patients with tinea corporis/tinea cruris were randomized into two groups to receive topical luliconazole cream once daily for 2 weeks or topical clotrimazole cream twice daily for 4 weeks. Scrapings from lesion were taken for mycological assessment. Clinical and mycological cure was assessed at each visit. Results: Each group had 50 patients. At the end of 1st week, the mycological cure was 78% in luliconazole and 12% in clotrimazole (P < 0.05) and complete clearance was achieved in 11 patients (22%) in luliconazole group. By the end, 98% got cured in luliconazole group and 80% in the clotrimazole group (P < 0.05). Relapse occurred in 20% in clotrimazole group as against 4% in luliconazole group (P < 0.05). Both groups showed only mild application site reactions except one patient who developed hypersensitivity to clotrimazole. Conclusions: Topical luliconazole was better in achieving faster mycological and clinical cure with lower relapse.

Comparative assessment of the efficacy of topical ketoconazole and topical luliconazole in cases of pityriasis versicolor at a tertiary care hospital in eastern India: A prospective, open, randomized controlled trial.

Comparative assessment of the efficacy of topical ketoconazole and topical luliconazole in cases of pityriasis versicolor at a tertiary care hospital in eastern India: A prospective, open, randomized controlled trial.

A critical appraisal of once-daily topical luliconazole for the treatment of superficial fungal infections.

Luliconazole is a novel imidazole derivative, which has demonstrated in vitro efficacy against dermatophytes and Candida. The results from Phase III trials show that luliconazole 1% cream applied once daily for 2 weeks successfully resolved the clinical signs and symptoms as well as eradicated the pathologic fungi, which cause tinea pedis. A 1-week treatment with luliconazole 1% cream also produced favorable clinical and mycological results in clinical trials for tinea corporis and tinea cruris. Across trials, adverse events consisted mainly of localized reactions following application. The development of a new antifungal agent is timely due to mounting resistance among existing treatments. Because luliconazole requires a short duration of treatment, it may assist in reducing disease recurrence as a result of patient nonadherence.

Once-daily luliconazole cream 1% for the treatment of interdigital tinea pedis

Luliconazole is an imidazole antifungal agent with a unique chemical structure. In this article, we summarize the in vitro data, animal studies and clinical trial data relating to the use of topical luliconazole cream 1% in the treatment of tinea pedis. Preclinical studies have demonstrated potent activity against dermatophytes. Luliconazole has strong fungicidal activity against Trichophyton spp., similar to that seen with terbinafine. Evidence from clinical trials in tinea pedis have shown once-daily application of luliconazole cream 1% for 14 days to be effective and well tolerated.

Novel in vivo observations on double acting points of luliconazole on Trichophyton rubrum: an ultrastructural study.

Scales from lesional skin of 12 patients with tinea pedis were investigated by scanning electron microscopy (SEM) and transmission electron microscopy (TEM) to gain an insight into the spatial and morphological changes of dermatophytes after application of a clinical dosage of topical luliconazole 1% cream (Lulicon® cream 1%). In all cases, Trichophyton rubrum was identified. The scales from the lesions collected before and after topical luliconazole application were fixed with glutaraldehyde and subjected to SEM and TEM. For SEM, fixed specimens were first placed in 1N-KOH and then post-fixed and observed. SEM showed a swollen appearance of fungal hyphae as an early change, and then shrinkage of them showing a flattened and twisted appearance as a later change. TEM showed cell wall alterations with initial development of and accumulation of a granular structure in the outermost layer and subsequent amorphous and electron-lucent change of the thickened inner part of the cell wall. This is the first report of dramatic morphological changes of T. rubrum before and after topical luliconazole application in vivo demonstrated by SEM and TEM. We hypothesize that luliconazole has double acting points, on the plasma membrane and cell wall, of dermatophyte hyphae.