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Safin, who will retire at the end of the year, is scheduled to play another eight tournaments.
"I'm tired of the tour, tired of staying at hotels and tired of traveling...I've had enough now," the Russian said after having lost the second set tie-break 8-6 on the Swedish clay. Asked by the Swedish news agency TT if he would be interested in a coaching career, Safin replied: "I am tired of everything that has to do with racquets and balls. I want to do something completely different."
Safin now has a 0-3 record against Almagro, all of the defeats having come on clay.
Tommy Robredo, another Spaniard, began his quest for a third Swedish Open title by easily beating Australian Peter Luczak 6-2, 6-3 in a second round match. Robredo, a winner here last year and in 2006, faces Safin's compatriot Teimuraz Gabashvili in the last eight.
Swede Robin Soderling, the second seed, beat Belgian Kristof Vliegen 6-2, 6-3 in just 55 minutes in another second round encounter.
"I played OK," Soderling said. "The last game was tough. I was a bit lucky. I didn't hit that overhead clean. It's so fun to play here before a sellout crowd and feel the support."
In Palermo, Italy, top-seeded Flavia Pennetta paid back Italian compatriot Roberta Vinci for a crushing loss in April by winning 7-5, 6-1 to reach the Palermo Open quarterfinals on Wednesday.
Pennetta won only three games against Vinci at Barcelona three months ago, but this time broke her seven times to even their head-to-heads at 3-3.
Seventh-seeded Aravane Rezai of France also won her second-round match, overcoming Varvara Lepchenko of the United States 6-7 (2), 6-4, 6-2 in just under three hours.
However, sixth-seeded Ekaterina Makarova of Russia fell to Olga Govortsova of Belarus 2-6, 2-6 in 44 minutes, and 2006 runner-up Tathiana Garbin of Italy ended the winning run of Maria Jose Martinez Sanchez of Spain 6-2, 6-3. Martinez Sanchez won the Swedish Open on Saturday.
Second-seeded Patty Schnyder, making her first appearance at Palermo since she won on debut as the top seed in 1998, defeated Russian teenager Anastasia Pivovarova 6-4, 6-0 to open her account. The Swiss veteran was coming off the final at Budapest.