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 Table of Contents    
Year : 2014  |  Volume : 46  |  Issue : 2  |  Page : 147-151

Protective effect of ketamine against hemorrhagic cystitis in rats receiving ifosfamide

1 Department of Pediatric Oncology, Celal Bayar University, School of Medicine, Manisa, Turkey
2 Department of Pediatric Surgery, Celal Bayar University, School of Medicine, Manisa, Turkey
3 Department of Biochemistry, Celal Bayar University, School of Medicine, Manisa, Turkey
4 Department of Histology and Embriology, Celal Bayar University, School of Medicine, Manisa, Turkey
5 Department of Pediatrics, Celal Bayar University, School of Medicine, Manisa, Turkey

Date of Submission07-Dec-2012
Date of Decision27-Jan-2013
Date of Acceptance12-Jan-2014
Date of Web Publication24-Mar-2014

Correspondence Address:
Ali A Ozguven
Department of Pediatric Oncology, Celal Bayar University, School of Medicine, Manisa
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0253-7613.129301

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 » Abstract 

Objective: To investigate the possible protective effect of a single dose of ketamine and the synergistic effect between ketamine and 2-mercaptoethane sulfonate (mesna) against ifosfamide-induced hemorrhagic cystitis.
Materials and Methods: 35 adult female wistar rats were divided into five groups and pretreated with ketamine at 10 mg/kg and/or mesna 400 mg/kg 30 minutes before intraperitoneal injection of IFS (400 mg/kg) or with saline (control group). Hemorrhagic cystitis was evaluated 24 hours after IFS injection according to bladder wet weight (BWW), and microscopic changes, i.e. edema, hemorrhage, cellular infiltration, and urothelial desquamation. The markers of oxidative damage including nitric oxide (NO) and malondialdehyde (MDA) levels and the expressions of tumor necrosis factor alpha (TNF-α), interleukin 1-beta (IL-1β), inducible nitric oxide synthase (i-NOS) and endothelial nitric oxide synthase (e-NOS) were also assayed in the bladder tissues.
Results: Pretreatment with ketamine alone or ketamine in combination with mesna reduced the IFS-induced increase of BWW (58,47% and 63,33%, respectively, P < 0.05). IFS- induced microscopic alterations were also prevented by ketamine with or without mesna (P < 0.05). In addition, also statistically insignificant, the bladder tissue expressions of IL-1β were lower in ketamine and/or mesna-receiving groups (P > 0,05). The parameters of oxidative stress, the NO and the MDA contents of the bladder tissues of the study groups were not different.
Conclusion: The results of the present study suggest that a single dose of ketamine pretreatment attenuates experimental IFS-induced bladder damage. It is therefore necessary to investigate ketamine locally and systematically with various dosing schedulesin order to reduce the bladder damage secondary to oxazaphosphorine-alkylating agents and these results may widen the spectrum of ketamine.

Keywords: Hemorrhagic cystitis, Ifosfamide, ketamine, mesna, protective

How to cite this article:
Ozguven AA, Yilmaz O, Taneli F, Ulman C, Vatansever S, Onag A. Protective effect of ketamine against hemorrhagic cystitis in rats receiving ifosfamide. Indian J Pharmacol 2014;46:147-51

How to cite this URL:
Ozguven AA, Yilmaz O, Taneli F, Ulman C, Vatansever S, Onag A. Protective effect of ketamine against hemorrhagic cystitis in rats receiving ifosfamide. Indian J Pharmacol [serial online] 2014 [cited 2023 Dec 8];46:147-51. Available from: https://www.ijp-online.com/text.asp?2014/46/2/147/129301

 » Introduction Top

It is well known that intensive chemotherapy regimens can cause several morbidities such as febrile neutropenia, allergic reactions, cardiac and renal dysfunction. Hemorrhagic cystitis (HC) is one of the common complications seen in patients who receive conventional chemotheraphy regimens consisting of oxazaphosphorine alkylating agents. The underlying mechanism of ifosfamide (IFS) or cyclophosphamide-induced HC is the direct contact of uroepithelium with acrolein, a urotoxic metabolite of these agents. It was reported that some mediators such as tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) resulted in the elevation of nitric oxide (NO) which plays a major role in the pathogenesis of HC. [1]

2-mercaptoethane sulfonate (Mesna) is a drug commonly used for HC induced by oxazaphosphorine alkylating agents as it binds and inactivates acrolein. The incidence of HC after the administration of oxazaphosphorine alkylating agents without mesna prophylaxis was reported to be as high as 68%, on the other hand, even with mesna prophylaxis, the incidence of HC can reach between 5% and 30%. [2],[3],[4] Thus, new approaches are being investigated to understand the pathogenesis of HC and to determine its risk factors and steps for its prevention. [3],[5]

Ketamine is usually used for analgesic and anesthetic purposes but recent studies have shown an antiinflammatory action in sepsis, cardiac surgery and asthma. It exerts this effect by suppressing the serum level of TNF-α, IL-1β, IL-6, IL-10, free oxygen radical levels and the downregulation of i-NOS (inducible nitric oxide synthase) immunoreactivity in injured tissues. [6],[7],[8],[9]

The aim of the study was to evaluate whether or not a single dose of ketamine alone or in combination with mesna would protect against IFS-induced HC in an experimental model in rats.

 » Materials and Methods Top

A total of 35 adult female non-pregnant Wistar rats (200-250 g) were used in this prospective and randomized study, five groups of 7 rats each. The animals were procured from the Animal Laboratory of the Ege University Faculty of Medicine (Izmir, Turkey). The animals arrived at the laboratory 1 week before the experiment commenced and were randomly housed in five cages (seven/cage) for a week with food and water ad libitum. They were maintained on a 12-h light: dark cycle with lights on from 08:00 to 20:00 hr, at a room temperature of 20-22°C.

On the 7 th day of the study, water intake was restricted for all rats for 12 hours, except the control group. After this period of time, the following treatment was given to the groups:

Group 1 (control group) received only sterile saline

Group 2 (IFS group) received i.p. injections of IFS 400 mg/kg

Group 3 (IFS + mesna group) was pretreated with i.p. injections of mesna 400 mg/kg 30 minutes before i.p. injections of IFS 400 mg/kg

Group 4 (IFS + ketamine group) was pretreated with i.p. single doses of ketamine 10 mg/kg 30 minutes before i.p. injections of IFS 400 mg/kg and

Group 5 (IFS + mesna + ketamine group) was pretreated with i.p. injections of mesna 400 mg/kg and a single dose of ketamine 10 mg/kg 30 minutes before i.p. injections of IFS 400 mg/kg.

During the study period, the rats were observed closely in terms of activity, occurrance of diarrhea and infectious diseases. The rats were sacrified 24 hs after IFS injection and the bladders were removed. The bladder tissues were examined microscopically and also evaluated in terms of the immunoreactivities of TNF-α, IL-1β, i-NOS, e-NOS and NO and MDA (malonaldehyde). The animal experiment procedures were approved by the Animal Welfare and Research Committee of Ege University and compatible with the National Institutes of Health guidelines on the use of experimental animals. The study protocol was in accordance with the guidelines of the Declaration of Helsinki for the use of animal experiments and approved by the Committee on Research Animal Care of Ege University, Faculty of Medicine.

Measurement of Vesical Edema

For the evaluation of the vesical edema, the bladder wet weight (BWW) was measured as a parameter and reported as mean ± SEM/100 g body weight.

Microscopic Evaluation

The bladders of rats were fixed in 10% formalin and embedded in paraffin. On the day of examination, the bladder tissue sections were cut on a rotary microtome (RM 2135, Leica) and the slides were deparaffinized in xylenes for two changes of 30 minutes. Following the rehydration process, they were stained with hematoxylin and eosin (HE, Reagen). Histopathological analysis was evaluated by two histologists who were unaware of the study groups, in accordance with Gray's criteria. [10] A score of 0 indicated normal epithelium and absence of inflammatory cell infiltration and ulceration; 1, mild changes involving reduction of epithelial cells, flattening with submucosal edema, mild hemorrhage, and few ulcerations and 2, severe changes including mucosal erosion, inflammatory cell infiltration, fibrin deposition, hemorrhage, and multiple ulcerations.

Immunohistochemical Staining

Tissue sections (5 μm) from each rat were prepared for immunohistochemical staining. After incubation in a 60°C oven, the tissues were deparaffinized with xylene. The tissue sections were then incubated with monoclonal anti-TNF-α, anti-IL-1β, anti-i-NOS and anti-e-NOS antibodies overnight. The cytokine immunoreactivities was evaluated as very weakly positive (0 or ±), weakly positive (1 or +), moderately positive (2 or ++) strongly positive (3 or +++) through the use of the indirect immunoperoxidase staining method.

Biochemical Analysis

The indicators of oxidative stress, NO and MDA levels were measured in bladder tissues which were homogenized in appropriate buffers and used for the following assays.

To estimate the tissue NO production, biochemical assessments of stable NO oxidative metabolites, nitrite (NO2 -) and nitrate (NO3 -) were analyzed. Assessment of tissue nitrite and nitrate levels was based on the Griess method. [11] All procedures were performed at +4°C. Bladder samples were homogenized in ten times the tissue volume of ice-cold Tris-HCl buffer (50 mMol/L, pH 7.4). After homogenization, samples were deproteinized with the Somogy reagent, and supernatants were used. One aliquot of supernatant was used for nitrite assessment by diazotization of sulfanilamide and coupling to naphthylethylene diamine. Another aliquot of supernatant was taken for the determination of total nitrite and nitrate levels which were reduced by copper-coated cadmium granules in a glycine buffer at pH 9.7 and then by the diazotization of sulfanilamide and coupling to naphthylethylene diamine. Absorbance of the colored reaction product was measured at 545 nm with a spectrophotometer (Shimadzu, Kyoto, Japan). Nitrate levels were taken to be the differences between absorbance values of two aliquots. A standard curve was obtained with solutions containing 2-10 μmol/L sodium nitrate. The data in this study presents the sum of nitrite and nitrate levels and expressed as μmol/g wet tissue.

To estimate the bladder tissue MDA content, the samples were stored at -20°C and then were assessed using a modified version of the Stocks and Dormandy method of thiobarbituric acid-reactive substances that provided indirect measurement of lipid peroxidation of MDA content. [12],[13] The results are expressed as nmol/ml.

Statistical Analysis

The histological results were expressed as median (min-max) and the other data as mean. Evaluation of the BWW data was carried out by analysis of variance (ANOVA) followed by Bonferroni's test. Microscopic scores were analyzed initially using the non-parametric Kruskal-Wallis test to determine the differences between groups. The Mann-Whitney U test was used to compare the findings of immunohistochemical staining and the NO and MDA contents of the bladder tissues between two groups. P < 0.05 was accepted as being statistically significant. Analysis was performed using the SPSS program version 11.0.

 » Results Top

The groups were comparable in age, gender and body weight before the study commenced (P > 0.05).

Effect on Ifosfamide-induced Bladder Wet Weight

Intraperitoneal injection of IFS evoked an increase of 220.1% in bladder wet weight within 24 h of its administration as compared to the control group (P < 0.05). The increase in bladder wet weight due to IFS treatment was significantly inhibited by the treatment of mesna (54.2% reduction in group 3, P < 0.05), as well as ketamine in isolation and ketamine in combination with mesna (58.5 and 63.3% reduction in group 4 and 5, respectively, P < 0.05). The bladder weights of ketamine- and/or mesna-treated rats were comparable to those rats in the control group.

Microscopic Alterations of Ketamine and/or Mesna in Ifosfamide-induced Hemorrhagic Cystitis

While the transitional epithelium, the multiple layers of epithelial cells and the basement membrane that separates the epithelium from the underlying lamina propria of the bladders were preserved in control group (Gray's score for edema and hemorrhage; median = 0 (0-0), for both parameters), the bladder wall showed damage in different stages in IFS-treated animals [Figure 1]. When compared to the control group, multi-layered epithelia was breached in some areas in group 2 (IFS treated). It was also seen that the cells of uroepithelium and connective tissues that constituted the lamina propria developed significant edema (Gray's score; median = 2, P < 0.05) and hemorrhage (Gray's score; median = 2, P < 0.05) and its chromatine were dense. On histologic analyses of the IFS + mesna group (group 3), the uroepithelium thickness was diminished, most of the epitheial cells were edemetous but there was no uroepithelial erosion or connective tissue edema (Gray's score; median = 1, for both parameters). Similarly, on histologic analyses of the tissues of the IFS + ketamine group (group 4), ketamine reduced IFS-induced gross edema and hemorrhage significantly (Gray's score; median = 1, P < 0.05, for both parameters), the uroepithelium thickness was preserved and there was no ulceration in uroepithelium or connective tissue edema. The results of the histologic analyses of the IFS + mesna + ketamine group were similar, there was no significant difference in the histological findings of the groups treated with mesna and/or ketamine (P > 0.05; group 3 vs. 4, group 3 vs. 5) [Table 1]. Neither damage nor neutrophilic infiltration was observed in the connective tissues of any group.
Table 1: Effect of ketamine and mesna on histopathology of bladder tissue in ifosfamide-induced haemorrhagic cystitis (as per Grey's criteria10)

Click here to view
Figure 1: Histological analysis of representative bladder walls. (a) Control group which received only saline. (b) In group 2, ifosfamide at 400 mg/kg induced multi-layered epithelia destruction in some areas (arrow). And the cells of epithelium and connective tissue were edemetous and its chromatine were dense (stars). (c) In group 3, epitheial cells were edemetous (arrows) but there was no uroepithelial erosion. (d and e) The epithelium thickness was normal but cells were edemetous in some areas (arrows). There was no damage in uroepithelium and connective tissue were normal. (H and E, ×100)

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Immunohistochemical Analyses

When the findings of immunohistochemical staining of the bladder tissues were analyzed, the tissue IL-1β expression of group 2 were significantly higher than those of the control group, group 3 and group 4 (P < 0.001) [Table 2]. But tissue i-NOS and e-NOS expressions between the IFS-receiving groups were not significantly different (P > 0.05). In addition, the bladder tissue expressions of TNF and IL-1β of the study groups who were treated with IFS were higher than the control group, but these differences were statistically insignificant (P > 0.05).
Table 2: Effect of ketamine and mesna on the bladder tissue TNF, IL-1β, i-NOS and e-NOS expressions in ifosfamide-induced haemorrhagic cystitis (scale of 0 to 3)

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Biochemical Analyses

The mean bladder NO and MDA contents of the study groups are depicted in [Table 3]. As expected, bladder NO and MDA levels of group 2 (IFS treated) were higher than the control group, but the difference was statistically insignificant (P > 0.05). Similarly, when the mean bladder NO and MDA levels of the group 2 were compared with groups 3, 4 and 5, levels of the IFS group (group 2) were higher than the other groups but the differences was statistically insignificant (P > 0.05).
Table 3: Effect of ketamine and mesna on nitric oxide and malonaldehyde levels in ifosfamide-induced haemorrhagic cystitis

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 » Discussion Top

In our study, the protective effect of a single dose of ketamine against IFS-induced HC was demonstrated. The study suggests a previously unreported effect of ketamine in the prophylaxis of experimental ifosfamide-induced HC. Ketamine was reported to have urological toxicity when used daily for an extended period of time (3 to 6 months), but in our study, rats received only single dose of ketamine concurrently with ifosfamide, so the deleterious effect of the drug on the lower urinary tract was eliminated. [14],[15]

It was recently reported that ketamine has an anti-inflamatory effect but few studies exist which describe this effect. Shaked et al. [7] demonstrated that ketamine administration improved survival and suppressed the levels of proinflammatory mediators as TNF-α, IL-6, IL-1β and free oxygen radical levels in rats with gram-negative bacterial sepsis. Additionally, it was shown that ketamine suppresses the increase of IL-6 response which was correlated with the patient's clinical course during or after cardiopulmonary bypass. [8]

No study has investigated the protective role of ketamine on oxazophosphorine-induced bladder damage. In the present study, an IFS-induced increase in bladder wet weight was inhibited by ketamine at 10 mg/kg and by mesna at 400 mg/kg. We also showed that ketamine in isolation or in combination with mesna can diminish IFS-induced uroepithelium injury and these microscopic alterations were also supported by the lower tissue IL-1β expressions of the study groups treated by both the drugs. Our results are compatible with the results of the previous studies demonstrating the anti-inflammatory effect of ketamine. [7],[8],[9]

Souza et al. [16] demonstrated the role of platelet activating factor (PAF), TNF-α and IL-1β in the pathogenesis of HC induced by alkylating agents. These pro-inflammatory cytokines induce the expression of i-NOS in the cytoplasm of the bladder epithelial cell and increase NO production. This in turn results in overproduction of reactive oxygen species (ROS) and reactive nitrogen species, in particular peroxynitrite, as a final mediator of HC. [1],[17] Kawasaki et al. [18] demonstrated that ketamine significantly suppressed lipopolysaccharide (LPS)-induced TNF-α production in a dose-dependent manner in patient with sepsis. But in our study, the immunoreactivitiy of IL-1β in groups treated with ketamine or mesna were lower than the group 2 and 5 (P < 0.001) but there were no significant differences between groups in terms of the immunoreactivities of i-NOS, e-NOS and TNF-α (P > 0.05).

It is shown that the indicators of oxidative stress and the major product of lipid peroxidation of membrane fatty acids, NO and MDA, accumulate in damaged bladders in experimental cyclophosphamide-induced HC. [19],[20],[21] In an actively sensitized animal model, Zhu et al. [9] demonstrated that nebulized ketamine decreased IL-4 and NO levels and the expression of i-NOS in the inflamed airways and, as a result, ketamin-attenuated airway hyperresponsiveness and inflammation in experimental asthma. In contrast, Shibakawa et al. [22] demonstrated that ketamine reduced LPS-induced TNF-α production without significant inhibition of NO release in mixed glial cells. Salman et al. [23] also showed that ketamine was found to attenuate MDA production in acute ischaemia-reperfusion-induced lipid peroxidation in muscle tissue in rats. In the present study, even though the mean bladder NO and MDA contents of ketamine-treated rats were lower than the rats who received IFS only, these differences were not statistically significant. We also could not demonstrate any significant difference betwen NO and MDA contents and i-NOS activities of the bladder tissues of the study groups, but this result may be due to the insufficient number of the subjects in the study.

The histological examination clearly demonstrated that uroepithelial damage characterized with edema and hemorrhage was prevented by ketamine in isolation or combined with mesna. When compared with the effect of mesna, the protective effect of ketamine against IFS-induced uroepithelial damage was similar (P < 0.05). This protection may be due to decreased production of IL-1β and the decrease in proinflammatory cytokines in bladder which reduce the expression of i-NOS and NO and peroxynitrite production.

In summary, this is the first study investigating the protective effect of ketamine on IFS-induced HC. The results of the present study suggest that ketamine appears to ameliorate the inflammatory reaction in IFS-induced HC in an experimental animal model, even if it is used without mesna. As the anti-inflammatory actions of ketamine extend beyond merely anesthetic effects, it should be further tested locally or systemically with various dosing schedules to reduce the side effects of oxazaphosphorine-alkylating agents and these results may widen the spectrum of the potential uses of ketamine.

 » References Top

1.Batista CK, Mota JM, Souza ML, Leitao BT, Souza MH, Brito GA, et al. Amifostine and glutathione prevent ifosfamide- and acrolein-induced hemorrhagic cystitis. Cancer Chemother Pharmacol 2007;59:71-7.  Back to cited text no. 1
2.Mota JM, Brito GA, Loiola RT, Cunha FQ, Ribeiro Rde A. Interleukin-11 attenuates ifosfamide-induced hemorrhagic cystitis. Int Braz J Urol 2007;33:704-10.  Back to cited text no. 2
3.Skinner R. Chronic ifosfamide nephrotoxicity in children. Med Pediatr Oncol 2003;41:190-7.  Back to cited text no. 3
4.Ratliff TR, Willians RD. Hemorrhagic cystitis, chemotherapy, and bladder toxicity. J Urol 1998;159:1044.  Back to cited text no. 4
5.Vieira MM, Brito GA, Belarmino-Filho JN, Macedo FY, Nery EA, Cunha FQ, et al. Use of dexamethasone with mesna for the prevention of ifosfamide-induced hemorrhagic cystitis. Int J Urol 2003;10:595-602.  Back to cited text no. 5
6.Hirota K, Lambert DG. Ketamine: New uses for an old drug? Br J Anaesth 2011;107:123-6.  Back to cited text no. 6
7.Shaked G, Czeiger D, Dukhno O, Levy I, Artru AA, Shapira Y, et al. Ketamine improves survival and suppresses IL-6 and TNFalpha production in a model of Gram-negative bacterial sepsis in rats. Resuscitation 2004;62:237-42.  Back to cited text no. 7
8.Roytblat L, Talmor D, Rachinsky M, Greemberg L, Pekar A, Appelbaum A, et al. Ketamine attenuates the interleukin-6 response after cardiopulmonary bypass. Anesth Analg 1998;87:266-71.  Back to cited text no. 8
9.Zhu MM, Zhou QH, Zhu MH, Rong HB, Xu YM, Qian YN, et al. Effects of nebulized ketamine on allergen-induced airway hyperresponsiveness and inflammation in actively sensitized Brown-Norway rats. J Inflamm (Lond) 2007;4:10.  Back to cited text no. 9
10.Gray KJ, Engelmann UH, Johnson EH, Fishman IJ. Evaluation of misoprostol cytoprotection of the bladder with cyclophosphamide (Cytoxan) therapy. J Urol 1986;133:497-500.  Back to cited text no. 10
11.Cortas NK, Wakid NW. Determination of inorganic nitrate in serum and urine by a kinetic cadmium-reduction method. Clin Chem 1990;36:1440-3.  Back to cited text no. 11
12.Nacitarhan S, Ozben T, Tuncer N. Serum and urine malondialdehyde levels in NIDDM patients with and without hyperlipidemia. Free Radic Biol Med 1995;19:893-6.  Back to cited text no. 12
13.Stocs J, Dormandy TL. The autooxidation of human red cell lipids induced by hydrogen peroxide. Br J Haematol 1971;20:95-111.  Back to cited text no. 13
14.Tan S, Chan WM, Wai MS, Hui LK, Hui VW, James AE, et al. Ketamine effects on the urogenital system-Changes in the urinary bladder and sperm motility. Microsc Res Tech 2011;74:1192-8.  Back to cited text no. 14
15.Morgan CJ, Curran HV. Independent Scientific Committee on Drugs. Ketamine use: A review. Addiction 2012;107:27-38.  Back to cited text no. 15
16.Souza-Fiho MV, Lima MV, Pompeu MM, Ballejo G, Cunha FQ, Ribeiro RA. Involvement of nitric oxide in the pathogenesis of cyclophosphamide-induced hemorrhagic cystitis. Am J Pathol 1997;150:247-56.  Back to cited text no. 16
17.Korkmaz A, Topal T, Oter S. Pathophysiological aspects of cyclophosphamide and ifosfamide induced hemorrhagic cystitis; implication of reactive oxygen and nitrogen species as well as PARP activation. Cell Biol Toxicol 2007;23:303-12.  Back to cited text no. 17
18.Kawasaki T, Ogata M, Kawasaki C, Ogata J, Inoue Y, Shigematsu A. Ketamine suppresses proinflammatory cytokine production in human whole blood in vitro. Anesth Analg 1999;89:665-9.  Back to cited text no. 18
19.Topal T, Oztas Y, Korkmaz A, Sadir S, Oter S, Coskun O, et al. Melatonin ameliorates bladder damage induced by cyclophosphamide in rats. J Pineal Res 2005;38:272-7.  Back to cited text no. 19
20.Al-Yahya AA, Al-Majed AA, Gado AM, Daba MH, Al-Shabanah OA, Abd-Allah AR. Acacia Senegal gum exudate offers protection against cyclophosphamide-induced urinary bladder cytotoxicity. Oxid Med Cell Longev 2009;2:207-13.  Back to cited text no. 20
21.Ozcan A, Korkmaz A, Oter S, Coskun O. Contribution of flavonoid antioxidants to the preventive effect of mesna in cyclophosphamide-induced cystitis in rats. Arch Toxicol 2005;79:461-5.  Back to cited text no. 21
22.Shibakawa YS, Sasaki Y, Goshima Y, Echigo N, Kamiya Y, Kurahashi K, et al. Effects of ketamine and propofol on inflammatory responses of primary glial cell cultures stimulated with lipopolysaccharide. Br J Anaesth 2005;95:803-10.  Back to cited text no. 22
23.Salman AE, Dal D, Salman MA, Iskit AB, Aypar U. The effect of ketamine on acute muscular ischaemia reperfusion in rats. Eur J Anaesthesiol 2005;22:712-6.  Back to cited text no. 23


  [Figure 1]

  [Table 1], [Table 2], [Table 3]

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