[Non-transecting anastomotic urethroplasty for strictures of the bulbar urethra. Systematic review].

The results of using non-transecting anastomotic urethroplasty in men with bulbous urethral strictures are presented in the review. A total of 25 original publications were found, including 20 foreign and 5 Russian articles. The studies included from 1 to 358 patients who underwent anastomotic urethroplasty without transection of the corpus spongiosum (average number of patients in a study was 54). Etiological factors were indicated in 17 articles. Most studies (10 out of 17) indicated idiopathic etiology as the predominant one. There was no correlation between the results of the procedure and the etiology of urethral stricture. The mean length of urethral stricture in the vast majority of studies was less than 2 cm, and only in a few studies it was larger, with a maximum mean value of 3.9 cm. Postoperative complication rates were reported in 20 studies and ranged from 0% to 23.9% within one study (median 8.4%). In general, mild complications occurred, corresponding to category I-II according to the Clavien-Dindo classification. The incidence of erectile dysfunction was evaluated in 18 studies and ranged from 0% to 23% (average value of 6.5%). The success of non-transecting anastomotic urethroplasty averaged 94.7% (82-100%) with a median postoperative follow-up of 24.5 months (3-150 months). In 9 out of 25 studies, an additional comparison with transecting technique was done. In 6 studies, the superiority of the non-transecting technique in terms of treatment success and preservation of sexual function was found. The obtained results showed the high efficiency and safety of non-transecting anastomotic urethroplasty in case of short strictures of the bulbous urethra.

[Antibacterial prophylaxis with fosfomycin at the time of the urethral catheter removal after radical prostatectomy (prospective randomized trial)].

AIM: To evaluate the effect of antibacterial prophylaxis using oral fosfomycin during the removal of a urethral catheter after radical prostatectomy on the development of urinary tract infection, severity of leukocyturia and bacteriuria, as well as the severity of lower urinary tract symptoms. MATERIALS AND METHODS: A single-center, non-blind, prospective, randomized controlled trial was carried out. The main group included 40 patients, and the control group included 37 patients. In the group 1, patients received two doses of oral fosfomycin, 3 g, namely in the evening on the day of catheter removal (the first dose) and 48 hours after catheter removal (the second dose). In the group 2, patients did not receive any antibacterial prophylaxis after urethral catheter removal. The endpoints of the study were confirmed episodes of urinary tract infection within 1 month after removal of the urethral catheter, leukocyturia and bacteriuria in urinalysis/urine culture) and severity of the lower urinary tract symptoms assessed by IPSS questionnaire. RESULTS: In the group 2, urinary tract infection was noted in 17.1%, while in the group 2 only in 2.6% of patients (p=0.032). Leukocyturia and bacteriuria were significantly less common in the group receiving antibacterial prophylaxis with fosfomycin (18.4% vs. 48.6%, respectively; p=0.006). Positive urine culture was observed in 7.9% vs. 25.7%, respectively (p=0.035). Four weeks after removal of the urethral catheter, the average IPSS score was significantly higher in the group 2 (13.2 vs. 9.5 points; p=0.002). There were no cases of allergic reaction and pseudomembranous colitis associated with C. difficile in both groups. Diarrhea cured with sorbents was noted in 2 patients (5.2%) in fosfomycin group. CONCLUSION: Antibacterial prophylaxis using two oral doses of fosfomycin 3 g on the day of urethral catheter removal and 48 hours after catheter removal after radical prostatectomy appears to be an effective scheme that reduces the incidence of urinary tract infection and the severity of lower urinary tract symptoms, and is characterized by a minimal risk of adverse events. It is necessary to carried out further research and develop clear recommendations for antibacterial prevention in urological interventions requiring prolonged urethral catheterization.

[Clinical and morphological assessment of the results of a standard robot-assisted nerve-sparing radical prostatectomy and with the use of Retzius-sparing technique].

OBJECTIVE: To compare the perioperative, functional, clinical and morphological results of a standard robot-assisted nerve-sparing radical prostatectomy and with the use of the Retzius-sparing technique. MATERIALS AND METHODS: A prospective analysis was performed of two groups of patients (n=54) who underwent nerve-sparing robot-assisted radical prostatectomy (period from 2017 to 2018). The first group included 29 patients who underwent nerve-sparing robot-assisted radical prostatectomy with Retzius-sparing technique, the second - 25 patients operated on according to the standard method of bilateral nerve-sparing radical prostatectomy. All patients were comparable in baseline characteristics. In all cases, patients had histologically verified localized prostate cancer pT2a-2c. RESULTS: In cases with use Retzius-sparing technique there is no statistically significant difference in the operation time (243.60 min vs 236.64 min, in groups 1 and 2, p>0.05) and intraoperative blood loss (131.20 ml vs 122.57 ml , in groups 1 and 2, p>0.05). Regarding the dynamics of the urinary continence recovery, the Retzius-sparing technique demonstrates advantages in speed and frequency at all follow-up periods (54.13% vs 41.81%; 68.12% vs 59.21%; 94.15% vs 90 , 63%; 98.54% vs 97.12%; 98.62% vs 97.31%; 98.83% vs 97.82% - in one week after removal of the urethral catheter, 1, 3, 6, 9, and 12 months in the first and second group, respectively). The frequency of erectile function recovery after 12 months was 82.17% and 71.14% in the first and second groups, respectively. CONCLUSIONS: Retzius-sparing robot-assisted prostatectomy superior to standard operation in the speed and timing of recovery of urine continence and erectile function.

[Feasibility and risks of nerve-sparing technique of radical prostatectomy in elderly patients].

OBJECTIVE: To evaluate the efficacy and safety of radical prostatectomy (RP) with nerve-saving technique (NST) in patients more or equal 65 years of age compared with a younger group of patients. MATERIALS AND METHODS: The study group comprised 117 patients more or equal 65 years old, the control group - 333 patients <65 years old, who underwent RP with unilateral or bilateral NST from January 2012 to December 2019. The analysis of pathomorphological results, complications rate, recurrence free survival (RFS) and the restoration of erectile function (EF) in both groups was performed. RESULTS: The majority of older patients belonged to intermediate and high risk groups of biochemical recurrence. Extracapsular tumor extension was significantly more often observed in the group more or equal 65 years of age: 16.2% and 6.9%, p=0.028. There were no differences between the two groups in the frequency of serious postoperative complications ( more or equal III class according to the Clavien-Dindo classification): 2.55% and 2.7%; p=0.94. The five-year RFS after RP was 95.4% in the group <65 years old and 92.1% in the group more or equal 65 years old (p=0.31). There was a moderate tendency to a slower recovery of EF in older patients: sufficient EF after 6 and 12 months was observed in 21.9% and 59.4% versus 33.3% and 73% in the group <65 years old (p=0.12). Minimal differences in EF were observed 24 months after RP with bilateral NST (84.2% and 87.9%), and more relevant differences with unilateral NST: 53.8% and 66.7% in the study and control group (p=0.033). CONCLUSIONS: The performance of RP with NST in elderly patients is not associated with additional oncological risks, while the restoration of EF is somewhat slowed down in comparison with a group of patients <65 years of age. Bilateral NST provides high potency recovery results regardless of age.

[Evaluation of orgasmic function in patients after radical prostatectomy].

INTRODUCTION: Radical prostatectomy (RP) remains the main treatment method of localized prostate cancer. Satisfactory functional results after RP are essential for both urologist and patient. Preservation of sexual function, particularly orgasmic function (OF) after RP is of the utmost importance today for patients and their sexual partners. MATERIALS AND METHODS: An analysis of 3- and 6-months functional results of 91 patients who underwent RP for prostate cancer is presented in this study. The influence of surgical approach, nerve-sparing surgery (NSS) and other factors for OF recovery was evaluated. RESULTS: OF recovered in 53,8% and 56% patients 3 and 6 months postoperatively, respectively. Positive influence of younger age and NSS on OF recovery was found. CONCLUSION: OF recovered in more than half of patients after RP. The young age, NSS were found to be predictors of RP recovery. Further research is required to determine the more relevant factors for OF recovery after RP.

[Oncological safety of nerve-sparing radical prostatectomy: evaluation of histopathological outcomes and recurrence-free survival].

OBJECTIVE: To evaluate histopathological outcomes and biochemical recurrence (BCR) free survival in patients after nerve-sparing radical prostatectomy (nsRP). MATERIALS AND METHODS: Prospective study group comprised 313 patients who underwent uni- or bilateral nsRP from 2014 to 2018; control group included 592 patients with clinically localized prostate cancer who underwent non-nsRP from 2014 to 2018. Mann-Whitney U-test was performed to assess continuous variables; chi-squared test was used for comparative analysis of categorical data. BCR free survival was evaluated with Kaplan-Meier method, log-rank test was used to compare survival outcomes. RESULTS: Adverse histopathological findings were lower in the study group: extracapsular extension was found in 9,4% and 18,75% (p<0,001), grade group upgrade in 23% and 29,3% (p=0,04), positive surgical margins (PSM) in 15% and 22,1% (p=0,01). Subanalysis according to cancer risk groups showed lower PSM rates in high-risk patients (15,6% and 30,3%, p=0,017) and tendency for higher PSM rates in low-risk patients in the study group with no significant difference (12,6% and 7%, p=0,16). BCR free survival after 12 months was 100% and 88,2%, after 20 months - 92,3% and 86,4%, p=0,04. PSM ratesin the study group were notsignificantly different depending on the type of surgery: 13,9% in robotic-assisted approach and 15,4% in retropubic approach, p=0,75. CONCLUSIONS: Relatively favorable histopathological outcomes and BCR free survival can be achieved after nsRP. However, obtained results could not be considered optimal and clearly indicate the need for further improvement of preoperative planning and intraoperative quality control of surgical treatment.

[Multiparametric magnetic resonance imaging markers of clinically significant prostate cancer].

Authors aimed to assess the correlation between the apparent diffusion coefficient (ADC of the tumor, ADC ratio) and final grade group (GG) after radical prostatectomy (RP), and to determine the threshold values of ADC for detecting clinically significant prostate cancer (PC) with subsequent evaluation in a prospective group. 118 patients with PC were included in the retrospective group. These patients underwent RP from 2012 to 2017 with preoperative 3 Tesla multiparametric MRI (mpMRT) with contrast enhancement in a single center. After analyzing all the MRI studies, the average values of tumor ADC and benign tissue ADC were calculated using the maps of ADC. The prospective part of the study included 60 patients with completed pre-biopsy mpMRI and subsequent RP from January 2018 to March 2019. The prospective part of the study demonstrated the effectiveness of applying the obtained diffusion coefficient thresholds. When used as a criterion for determining clinically significant prostate cancer (GG > 6), threshold value of ADC ratio had sensitivity, specificity, accuracy, positive predictive value and negative predictive value were 84%, 91%, 87%, 94% and 78% respectively.

[Influence of radical prostatectomy on orgasmic function].

This review is dedicated to orgasmic function which is one of the most intimate and crucial aspects of quality of life in patients who underwent radical prostatectomy for prostate cancer. The main risk factors that affect orgasmic function and recovery period after surgery are described.

[Non-transecting anastomotic urethroplasty].

The review analyzes the results of using non-transecting anastomotic urethroplasty in men with urethral strictures. Identified 14 original studies using this technique: 13 foreign and 1 Russian. In total, this technique was applied in 704 patients. This technique was used in 85% of cases with bulbar urethral stricture, in 15% - with posterior stricture.The average length of the urethral stricture in all studies was less than 2 cm, except for two works, where the average stricture length was 2.3 cm and 3.9 cm, respectively. This technique is equally successfully applied in all etiological variants of urethral stricture. The incidence of postoperative complications in all studies using non-transecting anastomotic urethroplastyaveraged 13.7%.Postoperative complications were mostly mild and corresponded to G1 according to Clavien-Dindo classification.According to 10 out of 14 studies that evaluated the effect of surgical treatment on the occurrence of erectile dysfunction (ED), the incidence of ED de novo was on average 13.4%. The success of treatment with the use of non-transecting anastomotic urethroplastyaveraged 95% (82-100%) with a median postoperative follow-up of 27 months (6-64 months). In 4 out of 14 studies, an additional comparison was transecting versus non-transecting techniques. Non-transecting technique was not inferior to transecting technique by any criterion, but, on the contrary, exceeded it in a number of indicators, including the dynamics of sexual function after surgery.On the basis of available studies on the use of non-transecting anastomotic urethroplasty, this technique should be recognized as a highly efficient and reasonably safe method for treating short urethral strictures and recommended for widespread clinical use.

[Diagnostic performance of 68GA-PSMA PET/CTin patients with prostate cancer].

INTRODUCTION: and aim. Most of the patients with biochemical recurrence after radical prostatectomy undergo salvage radiotherapy without guidance from imaging. In recent years, there has been an increasing role of Gallium-68 prostate specific membrane antigen (68Ga-PSMA) positron emission tomography/computed tomography (PET/CT) imaging in the management of prostate cancer. This study aimed to investigate diagnostic performance of 68Ga-PSMA PET/CT in patients with biochemical recurrence after radical prostatectomy. MATERIALS AND METHODS: From 2016 to 2017, 19 prostate cancer patients were evaluated by 68Ga-PSMA PET/CT at the Urology Clinic of S.P Botkin City Clinical Hospital; 17 of them had a biochemical recurrence and needed restaging of the disease. The age, prostate specific antigen (PSA) values, therapy at the time of the study, and maximum standard uptake value (SUVmax) were evaluated. RESULTS: The median age of patients was 65 years (interquartile range (IQR) 58.5-70.5), the median total PSA level was 2.36 ng/mL (IQR 1.5-4.19). In 8 of 17 patients, the PSA values did not exceed 2 ng/ml. The median time after radical prostatectomy was 33.2 months. (IQR 12-54.5). Positive PET/CT sites of recurrence were detected in 15 of 17 patients. Nine patients had only one positive site, and in six patients several positive sites were detected. Four patients with PET/CT positive pelvic lymph nodes and/or retroperitoneal space underwent salvage lymphadenectomy. Histological findings confirmed the presence of malignant growth in 3 out of 4 cases. CONCLUSION: 68Ga-PSMA PET/CT is an effective tool for the early detection of oligometastatic lesions in recurrent prostate cancer.

[Quality of life in women after anterior pelvic exenteration].

60 women, who underwent anterior pelvic exenteration with different types of urine derivation since 2004 till 2014 years in urology department, RMAPO, S.P. Botkin city hospital, were included in retrospective investigation. Middle age of patients was 53,2+/-3 (32-68). 38 women with bladder cancer and 22 women with urinary injuries after radiation therapy underwent anterior pelvic exenteration. Aim of this work is to perform quality of life comparison of patients after anterior pelvic exenteration with different types of urine derivation. Patients were divided in 3 groups: 1-st group 39 (65%) women, who underwent Brickers operation, 2-nd group 19 (31,66% ) women, who had Studers operation and 3-rd group - 2 (3,34%), patients who underwent continent urine derivation with formation of catheterizing urinary reservoir. Questionnaire (SF-36) was used to evaluate quality of life. Observation period was from 2 to 10 years. Postsurgical lethality was 3%, 5-years survival rate was 60,9+/-15,8% and 5-years recurrence-free survival rate was 55,4+/-12,6%. We established that quality of life in women who underwent orthotopic urine derivation was higher than in patients who underwent incontinent ileoconduit formation. Better quality of life was demonstrated by women, who had catheterizing urinary reservoir, but it is difficult to compare this group with the others, because of small number of patients with heterotopic catheterizing reservoir. Regarding the results of our investigation we made next conclusions: In spite of difficult technique, high risk of postoperative complications and lethality, anterior pelvic exenteration provide 5-years survival rate for 70% of patients In locally advanced tumors of pelvic organs anterior pelvic exenteration is salvational operation and keep satisfactory quality of life Orthotopic intestinal urine derivation is better to provide satisfactory quality of life for patients with invasive bladder cancer. For women with urinary injuries after radiation therapy Brikers operation is better type of urine derivation, in special cases heterotopic catheterizing reservoirs can be made.

[HYPERBARIC OXYGEN THERAPY IN THE TREATMENT OF MALE INFERTILITY ASSOCIATED WITH INCREASED SPERM DNA FRAGMENTATION AND REACTIVE OXYGEN SPECIES IN SEMEN].

The aim of this study was to explore the potential of hyperbaric oxygenation (HBO) for reduction of sperm DNA fragmentation level and reactive oxygen species (ROS) in semen. The study included 90 men with idiopathic infertility. Patients of the treatment group (n = 60) underwent HBO before the vitro fertilization (IVF) procedure. In the control group (n = 30) IVF was carried out without prior cours of HBO. Sperm DNA fragmentation analysis was carried out using the TUNEL assay, the level of ROS in the ejaculate was measured by chemiluminescence. HBO treatment resulted in a significant decrease in the mean level of sperm DNA fragmentation from 33.2 ± 7.5 to 11.9 ± 5.9%, and the median ROS in sperm from 0.89 to 0.39 mV/s (p < 0.05). In the control group these changes were not statistically significant. Pregnancy after IVF occurred in 63.3% (38/60) of sexual partners of the treatment group men and in 36.7% (11/30) of the control group (p < 0.05). The high efficiency of HBO in overcoming the adverse effects of oxidative stress on sperm parameters allows us to consider it as a promising method for the treatment of men with idiopathic infertility.

[Comparative analysis of histological and long-term oncological outcomes after radical prostatectomy in patients matching johns hopkins and the royal marsden hospital criteria for active monitoring].

A retrospective comparative analysis of results of treatment of patients with prostate cancer who met the most stringent (Johns Hopkins - JH; 74 patients) and the most mild (Royal Marsden Hospital - RMH; 263 patients) selection criteria for the management according to the strategy of active monitoring was performed. Significant differences in the frequency of detection of adverse histological features and biochemical recurrence-free survival after radical prostatectomy in patients eligible for JH and RMH criteria were not identified. Extracapsular extension occurred in 2.7 and 4.9% (P=0,33), seminal vesicle invasion - in 1.4 and 2,6% (P=0.43), positive surgical margins - in 6, 8 and 7.2 % (P=0.56) Gleason score increase - at 6.8 and 9.1 % (P=0.49), respectively. Five-year disease-free survival rates were 95.7 and 95,8% (P=0.41). Regardless of the protocol selection for active monitoring, precise examination of patients and staging of the disease are absolutely necessary, as well as the future well-designed studies on the comparative analysis of the effectiveness of active monitoring and early curative treatment in the settings of national health care.

[Experience of male transobturator AdVance sling implantation in patients with stress urinary incontinence after radical prostatectomy].

For the period from April 2008 to March 2012, 12 men with mild-to-moderate and severe stress urinary incontinence underwent transobturator AdVance sling implantation. In the preoperative period, all patients underwent assessment, including history taking, physical, and instrumental and laboratory examination. Daily pad test was used as an objective method for the assessment of the degree of urinary incontinence. The use no more than one pad a day was considered as recovery, no more than 2 pads or reduction of the loss of urine by more than 50%--as an improvement. Median follow-up period was 28 months. The success of the operation was achieved in 91.7% of cases. Implantation of the sling led to the significant decrease of urine loss, the number of used pads and improvement of quality of life of patients. Infectious and inflammatory complications of acute urinary retention were not observed. Implantation of male transobturator AdVance sling is effective and safe treatment for patients with stress urinary incontinence after radical prostatectomy.

[Potentials for the combined therapy of urination disorders in men: the choice of optimal scheme of treatment].

Moderate to severe urination disorders occur in 13-29% of men, and their frequency increases progressively with age. The key for successful use of the capabilities of modern drug therapy is the understanding of the pathophysiological bases of urination disorders. Despite some successes of monotherapy with alpha-adrenoblockers and 5alpha-reductase inhibitors, combined use of drugs is appropriate, because the differences in mechanisms of action allows to simultaneously act on the smooth muscle tissue, causing its relax, and reduce the size of prostate by the induction of apoptosis, which ultimately allows to expect the maximum therapeutic effect. The goal of therapy in patients with BPH is not only a reduction in the severity of urination disorders, but the prevention of disease progression. Obviously, urination disorders in men are not always caused by an benign prostate hyperplasia. Hyperactive symptoms (primary and secondary, due to metabolic disorders in detrusor against the background of prolonged existence of bladder outlet obstruction) are revealed in significant proportion of men. In this cases, the use of M-anticholinergics is indicated. Administration of alpha-adrenoblockers and antimuscarinic drugs is one of potential variant of combined therapy. Thus, it is important to follow the principles of selectivity in patients with urination disorders. Modern pharmacotherapy has an arsenal of drugs, allowing to choose the drug therapy for patients with urination disorders depending on the prevalence of their types.

[Modified method of retropubic prostatectomy (RMAPE method)].

The article presents the results of the examination and treatment of 125 patients with benign prostatic hyperplasia who underwent surgery in the urological clinic of RMAPE. Retropubic adenomectomy according to the method proposed by the Clinic of Urology and Surgical Andrology of RMAPE was performed in 83 patients, and 42 patients underwent transvesical adenomectomy. In accordance with a number of parameters (timing of surgery, frequency of intra- and postoperative complications, extent of blood loss, duration of bladder drainage, length of hospital stay), a modified method of retropubic prostatectomy demonstrated significantly better results than transvesical adenomectomy.

[Retropubic adenomectomy in patients with a high level of prostate-specific antigen after prostatic biopsy].

Results of examination and treatment were analysed for 58 patients after retropubic adenomectomy performed from February 2008 to June 2010. The examination protocol included assessment of a total score of the scales IPSS and QoL, parameters of uroflowmetry, total PSA, the size of the prostate, number of prostatic biopsies in a high PSA level. The removed adenomatous tissue was examined histologically. By a PSA level, all the patients were divided into 3 groups. Group 1 - 18 patients with a preoperative PSA level above 10 ng/ml, group 2 - 23 patients with a PSA level from 4 to 10 ng/ml, group 3 - 17 control patients with PSA under 4 ng/ml. Mean age of the examinees was 67.7 +/- 7, 68.7 +/- 7.7, 67.9 +/- 8.9 years (p>0.05), respectively. A mean PSA level was 20.9 (10.3-53), 6.6 (4.1-9.9) and 2.4 (1.3-3.9) ng/ml (p<0.01), respectively. A mean size of the prostate was larger in group 1 patients than in the controls: 127.3 (82-185) cm3 versus 100.7 (81-134) cm3 (p<0.05). Median of the number of transrectal multifocal biopsies was 2 (1-7), 1 (1-2) and 0 in groupl, 2 and 3, respectively. Histological examination of the adenomatous tissue detected prostatic adenocarcinoma in 0, 1(4.3%) and 1(5.9%) patients, respectively, while chronic prostatitis at different stages was diagnosed in 6(33.3%), 7(30.3%) and 7(41.2%) patients, respectively. Thus, the above protocol of examination of patients with prostatic adenoma including measurement of a PSA level, conduction of finger rectal examination followed by prostatic biopsy (transrectal saturation procedure is preferable) provides performance of adenomectomy without a risk to miss a clinically significant prostatic cancer even in a PSA level above 10 ng/ml.

[Choice of an optimal free graft for replacement urethroplasty in extensive urethral strictures].

Irrespective of the type and properties of a free graft in urethroplasty, survival of the graft depends on blood circulation in the nutrient bed. We made an experimental trial to study engraftment of free grafts of buccal and lingual mucosa on different types of the nutrient bed. Free flaps (78 buccal and 86 lingual mucosa samples) were taken from 52 male Wistar rats (300 to 470 body mass). Grafting was made on different types of nutrient bed - skeletal muscle, subcutaneous fat and penile tunica albuginea. Histological examination of the grafts was made 2, 4, 7 and 14 days after transplantation. The process of engraftment followed all the stages of nonspecific inflammation. The alteration stage (48 hours) is characterized by marked epithelial atrophy, necrosis of most of the cross-striate muscular fibers of the graft, necrotic alterations of the nutrient bed, primarily in the suture area. Excudation and emigration (2-4 days)--by continued necrotic changes with infiltration of the graft with neutrophilic leukocytes, edema of the upper layer stroma and infiltrate extention on the nutrient bed. Proliferation (day 7)--by attenuation of necroinflammatory processes, decline of leukocyte infiltration, formation of blood vessels in the subepithelial base of the graft. Regeneration (day7-14)--by recovery of the epithelial graft layer, development of granulation tissue in the submucosal base. The best engraftment was registered on transplantation on penile tunica albuginea (buccal graft--93.4%, lingual one--88.9%). Successful implantation on the muscle occurred in 90.7% for buccal and 87.9% for lingual grafts. On fat tissue buccal transplant failed in 19, lingua--in 23.89% transplantations. Thus, staging in interaction between different grafts and types of nutrient bed do not depend on characteristics of the bed and graft. Necroinflammatory changes in the buccal graft change for proliferative processes earlier than in the lingual one. Proliferative and regenerative processes develop earlier on penile tunica albuginea. Alteration and exudation are more pronounced on subcutaneous fat.