- Department of Orthopedics, West China Hospital, Sichuan University, Chengdu Sichuan, 610041, P.R.China;
Citation: XIAO Qiang, ZHOU Zongke. Perioperative pain management of total hip arthroplasty. Chinese Journal of Reparative and Reconstructive Surgery, 2019, 33(9): 1190-1195. doi: 10.7507/1002-1892.201903026 Copy
1. | Parvizi J, Miller AG, Gandhi K. Multimodal pain management after total joint arthroplasty. J Bone Joint Surg (Am), 2011, 93(11): 1075-1084. |
2. | Tang H, Du H, Tang Q, et al. Chinese patients’ satisfaction with total hip arthroplasty: what is important and dissatisfactory? J Arthroplasty, 2014, 29(12): 2245-2250. |
3. | 沈彬, 翁习生, 廖刃, 等. 中国髋、膝关节置换术加速康复——围术期疼痛与睡眠管理专家共识. 中华骨与关节外科杂志, 2016, 9(2): 91-97. |
4. | DeLeo JA. Basic science of pain. J Bone Joint Surg (Am), 2006, 88(Suppl 2): 58-62. |
5. | Strom BL, Berlin JA, Kinman JL, et al. Parenteral ketorolac and risk of gastrointestinal and operative site bleeding. A postmarketing surveillance study. JAMA, 1996, 275(5): 376-382. |
6. | De Oliveira GS Jr, Agarwal D, Benzon HT. Perioperative single dose ketorolac to prevent postoperative pain: a meta-analysis of randomized trials. Anesth Analg, 2012, 114(2): 424-433. |
7. | Alexander R, El-Moalem HE, Gan TJ. Comparison of the morphine-sparing effects of diclofenac sodium and ketorolac tromethamine after major orthopedic surgery. J Clin Anesth, 2002, 14(3): 187-192. |
8. | Camu F, Beecher T, Recker DP, et al. Valdecoxib, a COX-2-specific inhibitor, is an efficacious, opioid-sparing analgesic in patients undergoing hip arthroplasty. Am J Ther, 2002, 9(1): 43-51. |
9. | 王海兴, 林子洪, 陈桂浩, 等. 塞来昔布对全髋关节置换患者术前疼痛影响的随机双盲对照研究. 中国矫形外科杂志, 2014, 22(4): 314-319. |
10. | Buvanendran A, Kroin JS, Tuman KJ, et al. Effects of perioperative administration of a selective cyclooxygenase 2 inhibitor on pain management and recovery of function after knee replacement: a randomized controlled trial. JAMA, 2003, 290(18): 2411-2418. |
11. | 沈彬, 唐新, 杨静, 等. 围手术期口服塞来昔布对全膝关节置换术后疼痛和功能康复的近期影响和安全性观察. 中华外科杂志, 2009, 47(2): 116-119. |
12. | 张辉, 陈俊, 陈帅, 等. 帕瑞昔布钠不同给药时机对 THA 患者超前镇痛的效果分析. 重庆医学, 2017, 46(18): 2495-2496. |
13. | 张亚鑫, 孙钰, 李小磊, 等. 艾瑞昔布超前镇痛对全髋关节置换术患者术后早期康复的影响. 江苏医药, 2018, 44(11): 1247-1249. |
14. | Kerr DR, Kohan L. Local infiltration analgesia: a technique for the control of acute postoperative pain following knee and hip surgery: a case study of 325 patients. Acta Orthop, 2008, 79(2): 174-183. |
15. | Aguirre J, Baulig B, Dora C, et al. Continuous epicapsular ropivacaine 0.3% infusion after minimally invasive hip arthroplasty: a prospective, randomized, double-blinded, placebo-controlled study comparing continuous wound infusion with morphine patient-controlled analgesia. Anesth Analg, 2012, 114(2): 456-461. |
16. | Specht K, Leonhardt JS, Revald P, et al. No evidence of a clinically important effect of adding local infusion analgesia administrated through a catheter in pain treatment after total hip arthroplasty. Acta Orthop, 2011, 82(3): 315-320. |
17. | Liu W, Cong R, Li X, et al. Reduced opioid consumption and improved early rehabilitation with local and intraarticular cocktail analgesic injection in total hip arthroplasty: a randomized controlled clinical trial. Pain Med, 2011, 12(3): 387-393. |
18. | Solovyova O, Lewis CG, Abrams JH, et al. Local infiltration analgesia followed by continuous infusion of local anesthetic solution for total hip arthroplasty: a prospective, randomized, double-blind, placebo-controlled study. J Bone Joint Surg (Am), 2013, 95(21): 1935-1941. |
19. | Hofstad JK, Winther SB, Rian T, et al. Perioperative local infiltration anesthesia with ropivacaine has no effect on postoperative pain after total hip arthroplasty. Acta Orthop, 2015, 86(6): 654-658. |
20. | Zoric L, Cuvillon P, Alonso S, et al. Single-shot intraoperative local anaesthetic infiltration does not reduce morphine consumption after total hip arthroplasty: a double-blinded placebo-controlled randomized study. Br J Anaesth, 2014, 112(4): 722-728. |
21. | Busch CA, Whitehouse MR, Shore BJ, et al. The efficacy of periarticular multimodal drug infiltration in total hip arthroplasty. Clin Orthop Relat Res, 2010, 468(8): 2152-2159. |
22. | Dobie I, Bennett D, Spence DJ, et al. Periarticular local anesthesia does not improve pain or mobility after THA. Clin Orthop Relat Res, 2012, 470(7): 1958-1965. |
23. | Villatte G, Engels E, Erivan R, et al. Effect of local anaesthetic wound infiltration on acute pain and bleeding after primary total hip arthroplasty: the EDIPO randomised controlled study. Int Orthop, 2016, 40(11): 2255-2260. |
24. | Lunn TH, Husted H, Solgaard S, et al. Intraoperative local infiltration analgesia for early analgesia after total hip arthroplasty: a randomized, double-blind, placebo-controlled trial. Reg Anesth Pain Med, 2011, 36(5): 424-429. |
25. | Murphy TP, Byrne DP, Curtin P, et al. Can a periarticular levobupivacaine injection reduce postoperative opiate consumption during primary hip arthroplasty? Clin Orthop Relat Res, 2012, 470(4): 1151-1157. |
26. | Marques EM, Jones HE, Elvers KT, et al. Local anaesthetic infiltration for peri-operative pain control in total hip and knee replacement: systematic review and meta-analyses of short- and long-term effectiveness. BMC Musculoskelet Disord, 2014, 15: 220. |
27. | Højer Karisen AP, Geisler A, Petersen PL, et al. Postoperative pain treatment after total hip arthroplasty: a systematic review. Pain, 2015, 156(1): 8-30. |
28. | Møiniche S, Mikkelsen S, Wetterslev J, et al. A qualitative systematic review of incisional local anaesthesia for postoperative pain relief after abdominal operations. Br J Anaesth, 1998, 81(3): 377-383. |
29. | Richard BM, Rickert DE, Newton PE, et al. Safety evaluation of EXPAREL (DepoFoam Bupivacaine) administered by repeated subcutaneous injection in rabbits and dogs: species comparison. J Drug Deliv, 2011, 2011: 467429. |
30. | Domb BG, Gupta A, Hammarstedt JE, et al. The effect of liposomal bupivacaine injection during total hip arthroplasty: a controlled cohort study. BMC Musculoskelet Disord, 2014, 15: 310. |
31. | Zhang X, Yang Q, Zhang Z. The efficiency and safety of local liposomal bupivacaine infiltration for pain control in total hip arthroplasty: A systematic review and meta-analysis. Medicine (Baltimore), 2017, 96(49): e8433. |
32. | Saito N, Horiuchi H, Kobayashi S, et al. Continuous local cooling for pain relief following total hip arthroplasty. J Arthroplasty, 2004, 19(3): 334-337. |
33. | Ni SH, Jiang WT, Guo L, et al. Cryotherapy on postoperative rehabilitation of joint arthroplasty. Knee Surg Sports Traumatol Arthrosc, 2015, 23(11): 3354-3361. |
34. | Viscusi ER, Siccardi M, Damaraju CV, et al. The safety and efficacy of fentanyl iontophoretic transdermal system compared with morphine intravenous patient-controlled analgesia for postoperative pain management: an analysis of pooled data from three randomized, active-controlled clinical studies. Anesth Analg, 2007, 105(5): 1428-1436. |
35. | Hartrick CT, Bourne MH, Gargiulo K, et al. Fentanyl iontophoretic transdermal system for acute-pain management after orthopedic surgery: a comparative study with morphine intravenous patient-controlled analgesia. Reg Anesth Pain Med, 2006, 31(6): 546-554. |
36. | Buckenmaier CC 3rd, Xenos JS, Nilsen SM. Lumbar plexus block with perineural catheter and sciatic nerve block for total hip arthroplasty. J Arthroplasty, 2002, 17(4): 499-502. |
37. | Kuchálik J, Magnuson A, Lundin A, et al. Local infiltration analgesia or femoral nerve block for postoperative pain management in patients undergoing total hip arthroplasty. A randomized, double-blind study. Scand J Pain, 2017, 16: 223-230. |
38. | Fahs AM, Koueiter DM, Kurdziel MD, et al. Psoas compartment block vs periarticular local anesthetic infiltration for pain management after anterior total hip arthroplasty: a prospective, randomized study. J Arthroplasty, 2018, 33(7): 2192-2196. |
39. | Gasanova I, Alexander JC, Estrera K, et al. Ultrasound-guided suprainguinal fascia iliaca compartment block versus periarticular infiltration for pain management after total hip arthroplasty: a randomized controlled trial. Reg Anesth Pain Med, 2019, 44(2): 206-211. |
40. | Thybo KH, Mathiesen O, Dahl JB, et al. Lateral femoral cutaneous nerve block after total hip arthroplasty: a randomised trial. Acta Anaesthesiol Scand, 2016, 60(9): 1297-1305. |
41. | Capdevila X, Bringuier S, Borgeat A. Infectious risk of continuous peripheral nerve blocks. Anesthesiology, 2009, 110(1): 182-188. |
42. | Horlocker TT. Complications of regional anesthesia and acute pain management. Anesthesiol Clin, 2011, 29(2): 257-278. |
43. | Jiménez-Almonte JH, Wyles CC, Wyles SP, et al. Is local infiltration analgesia superior to peripheral nerve blockade for pain management after THA: a network meta-analysis. Clin Orthop Relat Res, 2016, 474(2): 495-516. |
44. | Choi PT, Bhandari M, Scott J, et al. Epidural analgesia for pain relief following hip or knee replacement. Cochrane Database Syst Rev, 2003, (3): CD003071. |
45. | Cheah JW, Sing DC, Hansen EN, et al. Does intrathecal morphine in spinal anesthesia have a role in modern multimodal analgesia for primary total joint arthroplasty? J Arthroplasty, 2018, 33(6): 1693-1698. |
46. | Kuchálik J, Granath B, Ljunggren A, et al. Postoperative pain relief after total hip arthroplasty: a randomized, double-blind comparison between intrathecal morphine and local infiltration analgesia. Br J Anaesth, 2013, 111(5): 793-799. |
47. | Li F, Ma J, Kuang M, et al. The efficacy of pregabalin for the management of postoperative pain in primary total knee and hip arthroplasty: a meta-analysis. J Orthop Surg Res, 2017, 12(1): 49. |
48. | Duthie DJ, Nimmo WS. Adverse effects of opioid analgesic drugs. Br J Anaesth, 1987, 59(1): 61-77. |
49. | Wheeler M, Oderda GM, Ashburn MA, et al. Adverse events associated with postoperative opioid analgesia: a systematic review. J Pain, 2002, 3(3): 159-180. |
50. | Ghanem CI, Pérez MJ, Manautou JE, et al. Acetaminophen from liver to brain: New insights into drug pharmacological action and toxicity. Pharmacol Res, 2016, 109: 119-131. |
51. | Liang L, Cai Y, Li A, et al. The efficiency of intravenous acetaminophen for pain control following total knee and hip arthroplasty: A systematic review and meta-analysis. Medicine (Baltimore), 2017, 96(46): e8586. |
52. | Politi JR, Davis RL 2nd, Matrka AK. Randomized prospective trial comparing the use of intravenous versus oral acetaminophen in total joint arthroplasty. J Arthroplasty, 2017, 32(4): 1125-1127. |
53. | Moyer R, Ikert K, Long K, et al. The value of preoperative exercise and education for patients undergoing total hip and knee arthroplasty: a systematic review and meta-analysis. JBJS Rev, 2017, 5(12): e2. |
54. | Roehrs TA, Roth T. Increasing presurgery sleep reduces postsurgery pain and analgesic use following joint replacement: a feasibility study. Sleep Med, 2017, 33: 109-113. |
- 1. Parvizi J, Miller AG, Gandhi K. Multimodal pain management after total joint arthroplasty. J Bone Joint Surg (Am), 2011, 93(11): 1075-1084.
- 2. Tang H, Du H, Tang Q, et al. Chinese patients’ satisfaction with total hip arthroplasty: what is important and dissatisfactory? J Arthroplasty, 2014, 29(12): 2245-2250.
- 3. 沈彬, 翁习生, 廖刃, 等. 中国髋、膝关节置换术加速康复——围术期疼痛与睡眠管理专家共识. 中华骨与关节外科杂志, 2016, 9(2): 91-97.
- 4. DeLeo JA. Basic science of pain. J Bone Joint Surg (Am), 2006, 88(Suppl 2): 58-62.
- 5. Strom BL, Berlin JA, Kinman JL, et al. Parenteral ketorolac and risk of gastrointestinal and operative site bleeding. A postmarketing surveillance study. JAMA, 1996, 275(5): 376-382.
- 6. De Oliveira GS Jr, Agarwal D, Benzon HT. Perioperative single dose ketorolac to prevent postoperative pain: a meta-analysis of randomized trials. Anesth Analg, 2012, 114(2): 424-433.
- 7. Alexander R, El-Moalem HE, Gan TJ. Comparison of the morphine-sparing effects of diclofenac sodium and ketorolac tromethamine after major orthopedic surgery. J Clin Anesth, 2002, 14(3): 187-192.
- 8. Camu F, Beecher T, Recker DP, et al. Valdecoxib, a COX-2-specific inhibitor, is an efficacious, opioid-sparing analgesic in patients undergoing hip arthroplasty. Am J Ther, 2002, 9(1): 43-51.
- 9. 王海兴, 林子洪, 陈桂浩, 等. 塞来昔布对全髋关节置换患者术前疼痛影响的随机双盲对照研究. 中国矫形外科杂志, 2014, 22(4): 314-319.
- 10. Buvanendran A, Kroin JS, Tuman KJ, et al. Effects of perioperative administration of a selective cyclooxygenase 2 inhibitor on pain management and recovery of function after knee replacement: a randomized controlled trial. JAMA, 2003, 290(18): 2411-2418.
- 11. 沈彬, 唐新, 杨静, 等. 围手术期口服塞来昔布对全膝关节置换术后疼痛和功能康复的近期影响和安全性观察. 中华外科杂志, 2009, 47(2): 116-119.
- 12. 张辉, 陈俊, 陈帅, 等. 帕瑞昔布钠不同给药时机对 THA 患者超前镇痛的效果分析. 重庆医学, 2017, 46(18): 2495-2496.
- 13. 张亚鑫, 孙钰, 李小磊, 等. 艾瑞昔布超前镇痛对全髋关节置换术患者术后早期康复的影响. 江苏医药, 2018, 44(11): 1247-1249.
- 14. Kerr DR, Kohan L. Local infiltration analgesia: a technique for the control of acute postoperative pain following knee and hip surgery: a case study of 325 patients. Acta Orthop, 2008, 79(2): 174-183.
- 15. Aguirre J, Baulig B, Dora C, et al. Continuous epicapsular ropivacaine 0.3% infusion after minimally invasive hip arthroplasty: a prospective, randomized, double-blinded, placebo-controlled study comparing continuous wound infusion with morphine patient-controlled analgesia. Anesth Analg, 2012, 114(2): 456-461.
- 16. Specht K, Leonhardt JS, Revald P, et al. No evidence of a clinically important effect of adding local infusion analgesia administrated through a catheter in pain treatment after total hip arthroplasty. Acta Orthop, 2011, 82(3): 315-320.
- 17. Liu W, Cong R, Li X, et al. Reduced opioid consumption and improved early rehabilitation with local and intraarticular cocktail analgesic injection in total hip arthroplasty: a randomized controlled clinical trial. Pain Med, 2011, 12(3): 387-393.
- 18. Solovyova O, Lewis CG, Abrams JH, et al. Local infiltration analgesia followed by continuous infusion of local anesthetic solution for total hip arthroplasty: a prospective, randomized, double-blind, placebo-controlled study. J Bone Joint Surg (Am), 2013, 95(21): 1935-1941.
- 19. Hofstad JK, Winther SB, Rian T, et al. Perioperative local infiltration anesthesia with ropivacaine has no effect on postoperative pain after total hip arthroplasty. Acta Orthop, 2015, 86(6): 654-658.
- 20. Zoric L, Cuvillon P, Alonso S, et al. Single-shot intraoperative local anaesthetic infiltration does not reduce morphine consumption after total hip arthroplasty: a double-blinded placebo-controlled randomized study. Br J Anaesth, 2014, 112(4): 722-728.
- 21. Busch CA, Whitehouse MR, Shore BJ, et al. The efficacy of periarticular multimodal drug infiltration in total hip arthroplasty. Clin Orthop Relat Res, 2010, 468(8): 2152-2159.
- 22. Dobie I, Bennett D, Spence DJ, et al. Periarticular local anesthesia does not improve pain or mobility after THA. Clin Orthop Relat Res, 2012, 470(7): 1958-1965.
- 23. Villatte G, Engels E, Erivan R, et al. Effect of local anaesthetic wound infiltration on acute pain and bleeding after primary total hip arthroplasty: the EDIPO randomised controlled study. Int Orthop, 2016, 40(11): 2255-2260.
- 24. Lunn TH, Husted H, Solgaard S, et al. Intraoperative local infiltration analgesia for early analgesia after total hip arthroplasty: a randomized, double-blind, placebo-controlled trial. Reg Anesth Pain Med, 2011, 36(5): 424-429.
- 25. Murphy TP, Byrne DP, Curtin P, et al. Can a periarticular levobupivacaine injection reduce postoperative opiate consumption during primary hip arthroplasty? Clin Orthop Relat Res, 2012, 470(4): 1151-1157.
- 26. Marques EM, Jones HE, Elvers KT, et al. Local anaesthetic infiltration for peri-operative pain control in total hip and knee replacement: systematic review and meta-analyses of short- and long-term effectiveness. BMC Musculoskelet Disord, 2014, 15: 220.
- 27. Højer Karisen AP, Geisler A, Petersen PL, et al. Postoperative pain treatment after total hip arthroplasty: a systematic review. Pain, 2015, 156(1): 8-30.
- 28. Møiniche S, Mikkelsen S, Wetterslev J, et al. A qualitative systematic review of incisional local anaesthesia for postoperative pain relief after abdominal operations. Br J Anaesth, 1998, 81(3): 377-383.
- 29. Richard BM, Rickert DE, Newton PE, et al. Safety evaluation of EXPAREL (DepoFoam Bupivacaine) administered by repeated subcutaneous injection in rabbits and dogs: species comparison. J Drug Deliv, 2011, 2011: 467429.
- 30. Domb BG, Gupta A, Hammarstedt JE, et al. The effect of liposomal bupivacaine injection during total hip arthroplasty: a controlled cohort study. BMC Musculoskelet Disord, 2014, 15: 310.
- 31. Zhang X, Yang Q, Zhang Z. The efficiency and safety of local liposomal bupivacaine infiltration for pain control in total hip arthroplasty: A systematic review and meta-analysis. Medicine (Baltimore), 2017, 96(49): e8433.
- 32. Saito N, Horiuchi H, Kobayashi S, et al. Continuous local cooling for pain relief following total hip arthroplasty. J Arthroplasty, 2004, 19(3): 334-337.
- 33. Ni SH, Jiang WT, Guo L, et al. Cryotherapy on postoperative rehabilitation of joint arthroplasty. Knee Surg Sports Traumatol Arthrosc, 2015, 23(11): 3354-3361.
- 34. Viscusi ER, Siccardi M, Damaraju CV, et al. The safety and efficacy of fentanyl iontophoretic transdermal system compared with morphine intravenous patient-controlled analgesia for postoperative pain management: an analysis of pooled data from three randomized, active-controlled clinical studies. Anesth Analg, 2007, 105(5): 1428-1436.
- 35. Hartrick CT, Bourne MH, Gargiulo K, et al. Fentanyl iontophoretic transdermal system for acute-pain management after orthopedic surgery: a comparative study with morphine intravenous patient-controlled analgesia. Reg Anesth Pain Med, 2006, 31(6): 546-554.
- 36. Buckenmaier CC 3rd, Xenos JS, Nilsen SM. Lumbar plexus block with perineural catheter and sciatic nerve block for total hip arthroplasty. J Arthroplasty, 2002, 17(4): 499-502.
- 37. Kuchálik J, Magnuson A, Lundin A, et al. Local infiltration analgesia or femoral nerve block for postoperative pain management in patients undergoing total hip arthroplasty. A randomized, double-blind study. Scand J Pain, 2017, 16: 223-230.
- 38. Fahs AM, Koueiter DM, Kurdziel MD, et al. Psoas compartment block vs periarticular local anesthetic infiltration for pain management after anterior total hip arthroplasty: a prospective, randomized study. J Arthroplasty, 2018, 33(7): 2192-2196.
- 39. Gasanova I, Alexander JC, Estrera K, et al. Ultrasound-guided suprainguinal fascia iliaca compartment block versus periarticular infiltration for pain management after total hip arthroplasty: a randomized controlled trial. Reg Anesth Pain Med, 2019, 44(2): 206-211.
- 40. Thybo KH, Mathiesen O, Dahl JB, et al. Lateral femoral cutaneous nerve block after total hip arthroplasty: a randomised trial. Acta Anaesthesiol Scand, 2016, 60(9): 1297-1305.
- 41. Capdevila X, Bringuier S, Borgeat A. Infectious risk of continuous peripheral nerve blocks. Anesthesiology, 2009, 110(1): 182-188.
- 42. Horlocker TT. Complications of regional anesthesia and acute pain management. Anesthesiol Clin, 2011, 29(2): 257-278.
- 43. Jiménez-Almonte JH, Wyles CC, Wyles SP, et al. Is local infiltration analgesia superior to peripheral nerve blockade for pain management after THA: a network meta-analysis. Clin Orthop Relat Res, 2016, 474(2): 495-516.
- 44. Choi PT, Bhandari M, Scott J, et al. Epidural analgesia for pain relief following hip or knee replacement. Cochrane Database Syst Rev, 2003, (3): CD003071.
- 45. Cheah JW, Sing DC, Hansen EN, et al. Does intrathecal morphine in spinal anesthesia have a role in modern multimodal analgesia for primary total joint arthroplasty? J Arthroplasty, 2018, 33(6): 1693-1698.
- 46. Kuchálik J, Granath B, Ljunggren A, et al. Postoperative pain relief after total hip arthroplasty: a randomized, double-blind comparison between intrathecal morphine and local infiltration analgesia. Br J Anaesth, 2013, 111(5): 793-799.
- 47. Li F, Ma J, Kuang M, et al. The efficacy of pregabalin for the management of postoperative pain in primary total knee and hip arthroplasty: a meta-analysis. J Orthop Surg Res, 2017, 12(1): 49.
- 48. Duthie DJ, Nimmo WS. Adverse effects of opioid analgesic drugs. Br J Anaesth, 1987, 59(1): 61-77.
- 49. Wheeler M, Oderda GM, Ashburn MA, et al. Adverse events associated with postoperative opioid analgesia: a systematic review. J Pain, 2002, 3(3): 159-180.
- 50. Ghanem CI, Pérez MJ, Manautou JE, et al. Acetaminophen from liver to brain: New insights into drug pharmacological action and toxicity. Pharmacol Res, 2016, 109: 119-131.
- 51. Liang L, Cai Y, Li A, et al. The efficiency of intravenous acetaminophen for pain control following total knee and hip arthroplasty: A systematic review and meta-analysis. Medicine (Baltimore), 2017, 96(46): e8586.
- 52. Politi JR, Davis RL 2nd, Matrka AK. Randomized prospective trial comparing the use of intravenous versus oral acetaminophen in total joint arthroplasty. J Arthroplasty, 2017, 32(4): 1125-1127.
- 53. Moyer R, Ikert K, Long K, et al. The value of preoperative exercise and education for patients undergoing total hip and knee arthroplasty: a systematic review and meta-analysis. JBJS Rev, 2017, 5(12): e2.
- 54. Roehrs TA, Roth T. Increasing presurgery sleep reduces postsurgery pain and analgesic use following joint replacement: a feasibility study. Sleep Med, 2017, 33: 109-113.