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Now, the only things standing between Armstrong and a seventh consecutive Tour title are a time trial, two medium mountain stages and two mostly flat stages, including the last ride into Paris on Sunday.
Pereiro beat a fellow Spaniard, Xabier Zandio, and two other riders in a finishing sprint to win Tuesday's stage. Armstrong trailed in a group with his main rivals, keeping his overall lead over second-place Ivan Basso at 2 minutes, 46 seconds.
Armstrong's main rivals, sensing that their chances of catching the American are slipping away, tried testing him again on two main climbs in stage 16 from Mourenx to Pau, the last of three days in the Pyrenees that straddle France and Spain.
But Armstrong comfortably matched their uphill accelerations -- and cruised to the finish looking relaxed. He finished in a group with Basso, Jan Ullrich and other top riders, all 3:24 behind Pereiro.
Armstrong called it a "no chain" day -- meaning he felt so strong it seemed as if his bicycle had no chain.
"I felt amazing on the bike," Armstrong said. "It's always nice to get through the mountains, especially the second set of mountains. The big difficulties are done."
The Spaniard's victory, his first at the Tour, made up for his disappointment Sunday in the 15th stage, when he placed second, beaten in a finishing sprint by Armstrong's Discovery Channel teammate, George Hincapie.
Pereiro completed the 112.2-mile trek Tuesday in 4:38.40, this time coming out on top in a final sprint against three other riders.
Basso is looking to improve on his third-place finish last year. Mickael Rasmussen of Denmark is third, 3:09 behind Armstrong, and 1997 winner Ullrich is fourth overall, trailing Armstrong by 5:58.
Already, some rivals are pinning their hopes on next year -- when Armstrong will be retired.
"When Lance Armstrong, the sheriff, is no longer here, then we can think about doing something more," said Francisco Mancebo, a Spaniard who is fifth overall.
The stage Tuesday was marked by another crowd-related incident when a roadside spectator hit rider Andrey Kashechkin in the face, bloodying his nose. The angry Kazakh said after completing the stage that race organizers should improve security.
He was struck, apparently accidentally, by a spectator who was cheering the riders on an ascent.
Kashechkin pulled up and then headed a short way back down the climb to meet a race doctor following behind in a car. The doctor treated him for a nose bleed.
During the 15th stage Sunday, a spectator running alongside riders up another climb went under the wheels of a motorcycle carrying a TV cameraman taping the race.