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Indian qualifier Somdev Devvarman eliminated defending champion Alexandr Dolgopolov 6-3, 7-6 (7/4) on Tuesday at the $1.76 million ATP and WTA Washington Open.
World number 129 Devvarman, a two-time US college champion ranked 104 spots below Ukranian ninth seed Dolgopolov, advanced to the round of 16, where he could face US eighth seed John Isner on Thursday.
"I'm very happy. That guy is a tough player, no question," Devvarman said. "I played really well. in the beginning. he gave me a couple errors to break him.
"He fought back in the second set. I was serving well. It kept me in the match. I gave myself looks on his serve. It was just confidence."
Devvarman, who went to India after Wimbledon to work with a Chennai-based charity called "Life is a Ball," feels on top of his game.
"I'm pretty sharp," he said. "Physically for sure."
American Ryan Harrison ousted Australian former world number one Lleyton Hewitt 6-3, 7-5 to book a Wednesday second-round match against Argentine top seed Juan Martin Del Potro, a two-time Washington winner and the 2009 US Open champion.
If Del Potro advances, he would face 20-year-old Aussie Bernard Tomic in the round of 16. Tomic advanced with a 6-1, 6-3 victory over Belgium's David Goffin, avenging a first-round loss last year at Wimbledon.
"I played not so bad," Tomic said. "Very tough conditions. Very difficult to play 100 percent on these courts because it's so hot and so humid."
Two other Aussies won as well, with wildcard James Duckworth downing Japanese qualifier Yuichi Sugita 6-2, 6-2 and Marinko Matosevic ousting Russian 15th seed Nikolay Davydenko 6-4, 7-5.
Another Aussie qualifier, Samuel Groth, blasted 10 aces but lost as Canadian fourth seed Milos Raonic hit nine of his own in a 7-5, 6-4 triumph.
Japanese second seed Kei Nishikori, a career-best 11th in the rankings, will open with a second-round match Wednesday night against US wildcard Jack Sock, who beat Dutchman Igor Sijsling 6-4, 6-2.
"I'm going to just go out and play my game," Sock said. "If I'm playing well, I think I have a shot at a lot of guys."
Nishikori, who has never played or practiced with Sock, is rated a title threat by Del Potro.
"He is another big favorite to win the tournament," Del Potro said of Nishikori after a practice session with him. "He is playing really well."
US sixth seed Sam Querrey saved four match points to outlast Uzbek Denis Istomin 4-6, 6-3, 7-6 (11/9). He gets Bulgarian 11th seed Grigor Dimitrov in the third round.
"It was stressful but I'm glad to get through," Querrey said.
Women's top seed Angelique Kerber of Germany connected on only 39 percent of her first serves but still dominated US qualifier Irina Falconi 6-2, 6-3 to book a second-round date with American Melanie Oudin.
"It was difficult after such a long time without matches," said Kerber, who included a five-day Majorca vacation in her post-Wimbledon break. "I can improve more."
Britain's Heather Watson rallied past US qualifier Alexandra Mueller 6-7 (5/7), 6-4, 6-3 and will play for a quarter-final berth against French fourth seed Alize Cornet.
"It was a tough match," Watson said. "I'm just glad I'm alive for another day."